HoldsUp

FoundMyFitness · 2025-09-09 · Rhonda Patrick (host), Derek

How To Increase Your Testosterone Levels Naturally | Derek from MPMD

101 research-tied claims examined: 4 contradicted 5 overstated 5 context 76 supported 11 unverified

76

Supported by research

0:03:55Dereksupportedhigh

Testosterone concentrations are approximately 10 times higher in males than in females.

"this is the primary male, all but significantly impactful in females as well, hormone that is present at about 10x the concentrations in males" (said at 0:03:55)

Circulating serum testosterone concentrations in adult males are approximately 10 to 15 times higher than in adult premenopausal females. Population reference intervals established using liquid chromatography-tandem mass spectrometry (LC-MS/MS) demonstrate median testosterone levels of approximately 3,700 ng/L in men compared to 270 ng/L in premenopausal women (and 180 ng/L in postmenopausal women), aligning directly with the claim of a ~10-fold difference between sexes.

0:09:21Dereksupportedhigh

Pre-pubertal castration of males prevents epiphyseal growth plates from fully closing and leads to osteoporosis due to the lack of aromatization of testosterone to estrogen.

"They are osteoporotic as a consequence of a lack of sufficient aromatization into estrogen, and their growth plates, the epiphyseal growth plates, don't close fully because of that lack of aromatization in adolescence, which is facilitated essentially entirely by testosterone as a substrate" (said at 0:09:21)

The speaker's description of male skeletal endocrinology is accurate. In human males, circulating testosterone serves as the primary substrate for extraglandular and local aromatization into estrogen via the aromatase enzyme (CYP19A1). Estrogen acting via estrogen receptor alpha is required for epiphyseal fusion at the end of puberty, attainment of peak bone density, and maintenance of bone mass. Human genetic models of aromatase deficiency and estrogen receptor insensitivity, as well as androgen deprivation/castration, demonstrate persistent open epiphyseal growth plates (leading to prolonged linear growth and eunuchoid proportions) and severe early-onset osteoporosis.

0:14:15Dereksupportedhigh

Sex hormone-binding globulin (SHBG) binds approximately 60% of total testosterone, albumin binds about 38%, and free testosterone makes up roughly 2% to 3%.

"I think SHBG is about 60% of your total T will be bound by SHBG, and then like 38% is albumin, and then 2% to 3% roughly, depending on how much SHBG is produced and some other factors, is actually free testosterone." (said at 0:14:15)

The speaker's distribution of circulating testosterone fractions accurately reflects established clinical and endocrine physiology. In healthy adult men, approximately 40% to 65% (commonly cited around 60%) of circulating total testosterone is bound with high affinity to sex hormone-binding globulin (SHBG), approximately 35% to 55% (commonly cited around 38%) is loosely bound to albumin, and roughly 1% to 3% (typically ~2%) circulates in an unbound, free form.

0:15:10Dereksupportedhigh

Testosterone secretion follows a diurnal rhythm with peak levels occurring early in the morning and trough levels at night.

"Testosterone is in a pulsatile secretion fashion, so you would see in a diurnal rhythm chart showing the secretions of testosterone throughout the day, it kind of pulses out in waves. So you would have like the biggest pulse early in the morning, and then it kind of goes, ebbs and flows throughout the day until it reaches its low point later at night" (said at 0:15:10)

Testosterone secretion in healthy adult men follows a well-characterized diurnal pattern and pulsatile release driven by luteinizing hormone (LH). Circulating levels peak in the early morning hours and decline across the day, reaching nadir (trough) levels in the late afternoon and night.

0:24:35Dereksupportedhigh

Luteinizing hormone (LH) from the pituitary gland signals Leydig cells in the testes to produce testosterone.

"the LH from the pituitary signals to the Leydig cells to make the intratesticular testosterone." (said at 0:24:35)

The speaker's statement accurately describes a fundamental pathway of the male hypothalamic-pituitary-gonadal axis. Luteinizing hormone (LH) secreted by the anterior pituitary gland binds to specific LH receptors on Leydig cells in the testicular interstitium, stimulating intracellular signaling cascades (primarily via cAMP/protein kinase A and steroidogenic acute regulatory protein) that drive the synthesis and secretion of testosterone.

0:25:43Dereksupportedmoderate

The prevalence of varicoceles in males is approximately 15%.

"I think the prevalence in males is like 15% of males have a varicocele." (said at 0:25:43)

Published epidemiological literature and large population-based studies consistently estimate the prevalence of varicoceles at approximately 15% among healthy males in the general population. In a multicenter cross-sectional study of 7,035 young men from six European countries, 15.7% were diagnosed with a clinical varicocele (grades 1–3). Systematic reviews of varicocele epidemiology corroborate this baseline prevalence of approximately 15% in healthy men (rising to 35% or higher in men with primary infertility).

0:29:35Dereksupportedhigh

Dihydrotestosterone (DHT) has a higher binding affinity for SHBG than testosterone, and testosterone has a higher binding affinity for SHBG than estrogen.

"that has a much higher binding affinity for SHBG than testosterone does. And then testosterone has a much higher binding affinity for SHBG than estrogen does." (said at 0:29:35)

Sex hormone-binding globulin (SHBG) has the highest binding affinity for dihydrotestosterone (DHT), followed by testosterone, and then estradiol (estrogen). In human plasma studies measuring intrinsic association constants or relative binding activities, SHBG exhibits approximately 1.2- to 3-fold higher affinity for DHT than for testosterone, while its binding affinity for testosterone is roughly 3-fold higher than for estradiol (PMID: 3702439, PMID: 7190578).

0:07:14Dereksupportedmoderate

Supraphysiological levels of androgens induce dose-dependent neurotoxicity, adverse cardiac remodeling, and dyslipidemia.

"at higher levels, androgens will be neurotoxic in a dose-dependent manner past supra levels. It will cause cardiac remodeling in a negative manner, like all of the dyslipidemia, all of the negatives that you would hear about when it comes to anabolic steroid use to some extent at supra levels are going to be present from testosterone" (said at 0:07:14)

Published literature confirms that supraphysiological doses of androgens (including testosterone and synthetic anabolic-androgenic steroids) cause adverse cardiac remodeling, dyslipidemia, and neurotoxic effects. Evidence from in vitro and animal models demonstrates dose-dependent neurotoxicity and impaired neurite outgrowth from supraphysiologic androgen exposure, while human observational cohorts and clinical reviews establish that chronic supraphysiologic androgen abuse leads to pathological cardiac hypertrophy, myocardial fibrosis, systolic/diastolic dysfunction, and severe dyslipidemia.

0:26:13Dereksupportedmoderate

A varicocele impairs testicular thermoregulation and significantly impedes local testosterone production and fertility.

"and it inhibits thermoregulation and significantly impedes testosterone production locally and fertility." (said at 0:26:13)

Published urological literature supports that varicoceles disrupt the countercurrent heat-exchange system of the pampiniform plexus, leading to testicular hyperthermia. This elevated temperature, combined with associated oxidative stress and hypoxia, impairs Leydig cell function (reducing testosterone production) and damages Sertoli cells and germ cells, contributing to impaired spermatogenesis and reduced fertility.

0:30:18Dereksupportedhigh

Combined oral contraceptives increase SHBG levels in women, suppressing total testosterone by 50% to 60% and free testosterone by 70% to 80%.

"they're using things like combined oral contraceptives which crank SHBG through the roof through the liver interaction with the combined oral contraceptive pills... you'll see in adolescent women or women who are, you know, in full adulthood that are taking combined oral contraceptives, their total testosterone will suppress upwards of 50 to 60% and free testosterone upwards of like 70 to 80%." (said at 0:30:18)

Combined oral contraceptives (COCs) stimulate hepatic production of sex hormone-binding globulin (SHBG) via the estrogen component (ethinyl estradiol) while simultaneously suppressing gonadotropin-driven ovarian androgen production. A systematic review and meta-analysis of 42 studies comprising 1,495 healthy women (PMID: 24082040) confirmed that COC use significantly elevates SHBG (mean difference +99.1 nmol/L) and reduces circulating androgens, resulting in a mean 61% reduction in free testosterone (relative change 0.39) alongside substantial suppression of total testosterone (mean difference -0.49 nmol/L), with individual reductions frequently reaching the ranges cited by the speaker.

0:32:22Dereksupportedmoderate

Starting at age 30, a man's total testosterone declines by about 1% per year on average, while SHBG increases, causing free testosterone to decrease by up to 2% per year.

"when you hit 30 years old, your total testosterone will decline by 1% per year. But the reality of what makes this even worse is your SHBG levels will increase year-over-year proportionally faster, thus making the velocity of free testosterone decreases dramatically more so proportionally. So even though total test decreases by 1% a year, your free test will decrease by up to 2% per year." (said at 0:32:22)

The speaker's statement accurately reflects findings from major longitudinal and population cohort studies of male aging, such as the Massachusetts Male Aging Study (MMAS) and the Baltimore Longitudinal Study of Aging (BLSA). In the MMAS cohort, total testosterone decreased cross-sectionally at approximately 0.8% per year and longitudinally at 1.6% per year, while sex hormone-binding globulin (SHBG) increased at approximately 1.6% per year. Because of this concomitant rise in SHBG, free and bioavailable testosterone fell at a faster rate of approximately 2% per year cross-sectionally (and 2% to 3% longitudinally).

0:34:23Dereksupportedmoderate

Women typically produce about one-tenth the amount of androgens that men produce.

"Like your production is, you know, a tenth of males typically, and then if you are occupying all of your androgens because, you know, essentially the SHBG is going to with a much higher binding affinity mop up all your DHT and testosterone" (said at 0:34:23)

Physiological tracer and steroid kinetic studies demonstrate that androgen production and circulating concentrations in women are roughly one-tenth (approximately 5% to 12%) of those observed in men. For example, daily dihydrotestosterone (DHT) production in women averages approximately 0.05 mg/day compared to 0.39 mg/day in men (approximately one-eighth), and total testosterone production rates in adult females (approximately 0.25–0.30 mg/day) are approximately one-twentieth to one-tenth of adult male production rates (roughly 5–7 mg/day).

0:41:07Dereksupportedmoderate

Alcohol consumption directly inhibits steroidogenesis in the testicles via toxic and oxidative stress mechanisms.

"alcohol, you know, the direct toxicity effects of that does inhibit actual steroidogenesis in the testicles themselves... ultimately the testes are very affected by oxidative stress, and if you're not capable of handling that adequately, like it will reflect in your inadequate output of hormones locally." (said at 0:41:07)

Published literature confirms that alcohol exerts direct toxic effects on the testes, suppressing Leydig cell steroidogenesis and testosterone biosynthesis through oxidative stress mechanisms as well as central hypothalamic-pituitary-gonadal axis disruption.

0:45:32Dereksupportedhigh

Obesity elevates the aromatization of testosterone to estrogen in adipose tissue, which causes heightened negative feedback on the hypothalamic-pituitary-gonadal axis and suppresses testosterone production.

"men who are obese and women, if you have a significant amount of fat, it is going to elevate your aromatization, which is, you know, your conversion of testosterone to estrogen... And if you have a significantly elevated amount of estrogen being converted from your testosterone that you make because of how much fat you have, you are basically achieving the proportional increase in estrogen that is much higher than the amount of testosterone substrate that led to that conversion. So you have that signal telling your brain, 'Okay, we're good.' But the amount of testosterone you actually had to begin with was not good." (said at 0:45:32)

The speaker accurately describes the physiological mechanism underlying obesity-related male hypogonadotropic hypogonadism. Adipose tissue expresses the aromatase enzyme (encoded by CYP19A1), which converts androgens (such as testosterone) to estrogens (such as estradiol). In individuals with significant obesity, expanded adipose tissue increases overall aromatase activity. The resulting elevated estrogen exerts enhanced negative feedback on the hypothalamus and pituitary gland, suppressing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion, which subsequently reduces testicular testosterone production. This mechanism is supported by randomized controlled trials and clinical trials demonstrating that aromatase inhibitors (such as letrozole, anastrozole, and leflutrozole) block this conversion, lower estradiol, increase LH/FSH secretion, and successfully restore endogenous testosterone levels in men with obesity-associated hypogonadotropic hypogonadism.

0:54:40Dereksupportedmoderate

Endocrine-disrupting chemicals interact directly with estrogen and androgen receptors, acting as anti-androgens or anti-estrogens by occupying receptor binding sites.

"there is blatant evidence showing interactions with estrogen receptors with some of these compounds, as well as androgen receptors, which in turn will impede the ability of the actual hormones you produce to bind to those receptors and do what it needs to do. So you're like essentially competing with yourself for activity in the body. Like you're, you know, competing with these like even if they're like moot activity compounds, they still act as like anti-androgens or anti-estrogens via their occupying of receptors." (said at 0:54:40)

The claim accurately describes an established pharmacological mechanism of endocrine-disrupting chemicals (EDCs). Extensive in vitro competitive receptor-binding assays and molecular modeling demonstrate that many environmental EDCs (such as bisphenols, phthalates, pesticides, and parabens) bind directly into the ligand-binding pockets of estrogen receptor alpha/beta (ERα/ERβ) and the androgen receptor (AR). By occupying these sites, they can competitively block endogenous hormones (such as estradiol, testosterone, and dihydrotestosterone) and act as receptor antagonists or weak partial agonists.

0:58:56Dereksupportedhigh

All steroid hormones in the body, including testosterone and estradiol, are enzymatically derived from cholesterol as their biochemical precursor.

"there are like certain baseline requirements to serve as the substrate for producing cholesterol-derived steroids in the body, and these are all ultimately derived from cholesterol and then get cleaved and manipulated through enzymatic processes to make all the hormones in your body, including but not limited to testosterone, estradiol, etc." (said at 0:58:56)

Biochemical and endocrinological literature confirms that cholesterol is the universal parent precursor for all steroid hormones in the mammalian body. Through sequential enzymatic steps—beginning with the cleavage of cholesterol's side chain by mitochondrial cytochrome P450 side-chain cleavage enzyme (CYP11A1) to form pregnenolone—cholesterol is metabolized into glucocorticoids, mineralocorticoids, and sex steroids, including testosterone and estradiol.

0:45:43Dereksupportedmoderate

In males, negative feedback to the hypothalamus and pituitary regulating gonadotropin and testosterone production is primarily mediated by estradiol produced through aromatization, rather than by testosterone directly.

"This is more impactful in males because of how the brain gets signaled from estrogen, not testosterone directly as significantly. There's a bit of a nuance there, but in general, like you need adequate estrogen to tell your brain, "Okay, we're good. You don't need to make enough more testosterone because I have enough estrogen."" (said at 0:45:43)

Physiological studies in human males demonstrate that estradiol (produced via peripheral and central aromatization of testosterone) is a critical mediator of negative feedback on the hypothalamic-pituitary-gonadal axis. Selective aromatase inhibition (e.g., with anastrozole) substantially increases LH pulse frequency and amplitude and raises circulating testosterone, while in men with aromatase deficiency or pharmacological estrogen ablation, estradiol replacement restores hypothalamic GnRH pulse regulation and pituitary suppression. While testosterone itself also exerts direct androgen-receptor-mediated negative feedback on LH, estradiol is necessary for pituitary inhibition and is the primary sex-steroid regulator of FSH.

0:33:53Dereksupportedhigh

IGF-1 and thyroid hormones circulate bound to specific binding proteins in the body, meaning total circulating hormone levels can appear normal while free, biologically active hormone levels are significantly lower.

"Like you will have binding proteins for IGF-1, you'll have binding proteins for thyroid hormones. Like it's not uncommon to see people with like normal on-paper levels for certain hormones, but then when you dig deeper, all the free hormones are like proportionally horrible because they're all bound—the total production looks okay, but it's cuz it's factoring in all these like bound-up hormones that are unusable essentially." (said at 0:33:53)

The speaker accurately describes established endocrine principles regarding carrier proteins and the free hormone hypothesis. Both thyroid hormones (triiodothyronine and thyroxine) and insulin-like growth factor 1 (IGF-1) circulate primarily bound to high-affinity plasma proteins—such as thyroxine-binding globulin (TBG), transthyretin, and IGF-binding proteins (IGFBPs)—which sequester the majority of circulating hormone. Under the free hormone hypothesis, only the unbound (free) fraction is biologically active and directly available to target cell receptors. Variations in binding protein levels or binding affinity can cause total hormone levels to diverge significantly from the free, biologically active hormone concentrations.

1:01:46Dereksupportedmoderate

A lack of insulin signaling reduces the physiological capacity to suppress sex hormone binding globulin (SHBG).

"It's just like mechanistically this is what happens if you have a lack of insulin signaling. You will have less capacity to suppress the binding proteins." (said at 1:01:46)

Published experimental and human clinical studies demonstrate that insulin acts directly on hepatocytes to suppress the synthesis and secretion of sex hormone-binding globulin (SHBG). In cell culture models (such as HepG2 human hepatoma cells), insulin significantly inhibits baseline and hormone-stimulated SHBG production. In human interventional studies, suppressing insulin secretion (e.g., using diazoxide) results in a significant increase in circulating SHBG levels, confirming that insulin signaling physiologically suppresses SHBG.

1:06:26Dereksupportedmoderate

Vitamin D functions as a hormone and influences androgen receptor activity.

"vitamin D is a hormone, for example, and it does also affect androgen receptor activity and some like the capacity for androgens to do what they do, not just like the production of the amount of them." (said at 1:06:26)

Vitamin D in its active form (1,25-dihydroxyvitamin D3 or calcitriol) functions as a secosteroid hormone that binds to the nuclear vitamin D receptor (VDR). Molecular and cellular studies demonstrate crosstalk between VDR and androgen receptor (AR) signaling pathways, where active vitamin D signaling modulates AR expression, activity, and downstream target gene responses beyond simply altering circulating androgen levels.

1:16:56Dereksupportedhigh

Eurycomanone is the primary active bioactive constituent in Tongkat Ali.

"You want to look for one that is HPLC-tested for eurycomanone. That's the active ingredient in Tongkat Ali that actually has the bioactive effect that you're looking for." (said at 1:16:56)

Published phytochemical and pharmacological literature identifies eurycomanone as the major, primary bioactive quassinoid in Tongkat Ali (Eurycoma longifolia) responsible for its hormonal, spermatogenic, and aphrodisiac bioactivity. Furthermore, high-performance liquid chromatography (HPLC) is the standard, validated analytical method used commercially and in scientific research to standardize and verify the bioactive concentration of eurycomanone in E. longifolia extracts.

1:17:35Dereksupportedhigh

Primary hypogonadism cannot be treated or resolved with clomiphene, hCG, or hMG because the testes cannot produce testosterone in response to signaling.

"Primary hypogonadal, like you're going to probably be on exogenous testosterone and it's literally like testosterone. You can't fix it with any clomiphene. You can't fix it with hCG. You can't fix it with hMG. There's no other way around it." (said at 1:17:35)

Primary hypogonadism (hypergonadotropic hypogonadism) is defined by intrinsic testicular or Leydig cell failure, where the testes are unable to produce adequate testosterone despite elevated endogenous gonadotropin levels (LH and FSH). Therapies such as clomiphene citrate, human chorionic gonadotropin (hCG), and human menopausal gonadotropin (hMG) work either by stimulating pituitary LH/FSH release or directly mimicking gonadotropic signaling; because they rely on functional, responsive testicular tissue, they are effective only in secondary (hypogonadotropic/central) hypogonadism and cannot restore testosterone synthesis in primary testicular failure, which requires exogenous testosterone replacement therapy.

1:18:36Dereksupportedhigh

hCG acts as a functional luteinizing hormone (LH) mimic to stimulate testicular Leydig cells directly.

"So what he did was he used hCG, which was assessing, okay, are the testes responding to like a manual signal? And they were, and he's like replaced his hormones entirely by using a manual LH mimic essentially." (said at 1:18:36)

Human chorionic gonadotropin (hCG) acts as a functional agonist of the luteinizing hormone/choriogonadotropin receptor (LHCGR), which is expressed directly on testicular Leydig cells. Stimulation of LHCGR by hCG activates steroidogenesis and testosterone production, making it a standard pharmacological analogue of LH used clinically for both diagnostic evaluation of testicular reserve and hormone replacement in secondary hypogonadism.

  • supports: Luteinizing hormone receptor knockout mouse: What has it taught us? (Andrology 2026) · cited 9x in the literature
    "Luteinizing hormone (LH), along with its agonist choriongonadotropin (hCG) in humans, is the key hormone responsible for the tropic regulation of the gonadal function. LH and hCG act through their cognate receptor, the luteinizing hormone/choriongonadotropin receptor (LHCGR; more appropriately LHR in rodents lacking CG), located in the testis in Leydig cells and in the ovary in theca, luteal, and luteinizing granulosa cells." (abstract, passage verified)
    pubmedfull study (doi)
1:23:03Dereksupportedmoderate

Salivary cortisol measurements over multiple daily time points reflect stress response and cortisol dynamics more accurately than a single transient serum cortisol draw.

"Salivary cortisol levels are far more indicative of what's happening from a stress response standpoint than your like transient serum cortisol levels will be." (said at 1:23:03)

Salivary cortisol reflects the biologically active, unbound free cortisol fraction, whereas standard serum cortisol assays measure total cortisol (including the ~90% bound to cortisol-binding globulin and albumin), which can be confounded by changes in binding protein levels. In addition, isolated spot serum draws capture only an acute single point in time and can be influenced by the acute stress of venipuncture, whereas non-invasive salivary sampling allows repeated assessments across diurnal cycles and during dynamic stress response protocols.

1:23:30Dereksupportedlow

Shilajit supplementation enhances intratesticular antioxidant activity, reducing local reactive oxygen species and stress to support testosterone production.

"Shilajit seems to be impactful on intratesticular antioxidant activity, but it's another one that requires careful sourcing and it's also one that's like more speculative and indirect" (said at 1:23:30)

Preclinical animal models demonstrate that Shilajit supplementation enhances intratesticular antioxidant activity—upregulating Nrf-2 and superoxide dismutase (SOD) while reducing lipid peroxidation and testicular oxidative stress—to preserve steroidogenesis and testosterone biosynthesis. Human clinical studies support an increase in circulating total/free testosterone and a reduction in seminal markers of oxidative stress (malondialdehyde), though direct intratesticular measurement in humans remains indirect and limited primarily to rodent models.

1:29:58Dereksupportedhigh

Gonadotropin-releasing hormone (GnRH) secreted by the hypothalamus stimulates the pituitary gland to synthesize and release luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

"And then like upstream to that, there's the actual hypothalamus and the GnRH output, which is the thing that stimulates the pituitary to make the LH and the FSH." (said at 1:29:58)

The statement accurately reflects the fundamental physiology of the hypothalamic-pituitary-gonadal (HPG) axis. Gonadotropin-releasing hormone (GnRH) released from the hypothalamus acts on GnRH receptors in pituitary gonadotrope cells to stimulate the synthesis and secretion of both luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

1:35:10Rhonda Patrick (host)supportedhigh

The TRAVERSE trial showed that testosterone replacement therapy in middle-aged and older hypogonadal men did not increase the incidence of major adverse cardiovascular events compared to placebo.

"There's the TRAVERSE trial that came—that's kind of we got some pre-data here where it seems as though this is a very large trial, placebo-controlled, where it seems as though men—these are older men that were at least it seems to be hypogonadal, like they were low testosterone, and if they were given testosterone replacement therapy to a normal like physiological restoration range, there's no really adverse effects on cardiovascular outcomes." (said at 1:35:10)

The TRAVERSE trial (Lincoff et al., 2023) was a multicenter, randomized, double-blind, placebo-controlled noninferiority trial involving 5,246 men aged 45 to 80 years with hypogonadism (two fasting testosterone levels <300 ng/dL) and preexisting cardiovascular disease or high cardiovascular risk. Participants received daily transdermal testosterone gel (titrated to maintain testosterone levels between 350 and 750 ng/dL) or placebo. Over a mean follow-up of 33.0 months, a primary major adverse cardiac event occurred in 7.0% of men in the testosterone group versus 7.3% in the placebo group (hazard ratio, 0.96; 95% CI, 0.78 to 1.17; P<0.001 for noninferiority), confirming that testosterone replacement therapy did not increase major adverse cardiovascular events compared to placebo.

1:38:33Rhonda Patrick (host)supportedmoderate

Approximately 25% of men on testosterone replacement therapy develop elevated hematocrit or polycythemia.

"I mean, I think I've read studies where it's like almost 25% of men have thicker blood that are on testosterone replacement therapy. Doesn't necessarily mean it's like to the point where it has to be treated, but it is thicker, right? It is like the hematocrit is it's thicker." (said at 1:38:33)

The host's statement that nearly 25% of men on testosterone replacement therapy (TRT) develop elevated hematocrit (erythrocytosis or 'thicker blood'), even if not always requiring medical intervention, is well-supported by clinical literature. Testosterone stimulates erythropoiesis, and studies evaluating hematocrit elevation in men undergoing TRT report that approximately 20% to 25% reach a hematocrit threshold above 50% (with rates varying based on formulation, being higher with intramuscular injections than transdermal preparations), while severe polycythemia (hematocrit >54%) occurs in about 3% to 5% of patients.

1:39:30Dereksupportedhigh

Testosterone stimulates erythropoiesis in a dose-dependent manner.

"the thing to note is it should be expected that if you use more testosterone, you're going to have more erythropoiesis. Like that's literally what it does." (said at 1:39:30)

The claim is supported by randomized controlled trials in humans. Increasing doses of testosterone lead to dose-dependent, linear increases in red blood cell production, hemoglobin, and hematocrit levels in both young and older men.

1:47:05Dereksupportedmoderate

According to the androgen saturation model, increasing testosterone from hypogonadal to eugonadal levels (around 300+ ng/dL) stimulates prostate growth and increases PSA, but prostate androgen receptors saturate and further increases in testosterone do not dose-dependently increase prostate size.

"shows that if you go from hypogonadal to eugonadal or like the threshold of it, which is like, you know, on a reference range roughly like 300 plus nanograms per deciliter, going from hypo to that, that differential will be positively stimulating of like prostate growth, you know, PSA levels will go up, etc. But beyond that, you are not necessarily in a dose-dependent manner like a muscle or something going to be inducing size increases." (said at 1:47:05)

The speaker accurately describes the androgen saturation model proposed by Morgentaler and colleagues. Under this model, prostate tissue growth and PSA expression are highly sensitive to testosterone changes at low (castrate or severe hypogonadal) concentrations because androgen receptors (AR) are unsaturated. Maximal AR binding in the prostate occurs at a relatively low threshold (roughly 200–250 to ~300 ng/dL), after which the receptors are fully saturated, meaning further elevations into the normal or supraphysiological eugonadal range do not produce dose-dependent increases in prostate growth or PSA.

1:59:10Dereksupportedhigh

Oral formulations Tlando, Jatenzo, and Kyzatrex deliver testosterone undecanoate via lymphatic absorption without requiring 17-alpha-alkylation, avoiding the classic first-pass hepatotoxicity of older oral androgens.

"So there is three, I believe: Tlando, Jatenzo, and Kyzatrex. And they've basically managed to make a lymphatically absorbed testosterone undecanoate you can actually swallow orally, whereas back in the day, they would have had to make it hepatotoxic to actually make it through the liver through a first-pass metabolism and actually make it into circulation to any meaningful level. They'd have to like add like a 17-alpha-alkylated group to it and make it like a terrible for you oral steroid." (said at 1:59:10)

Modern oral testosterone undecanoate formulations (such as Jatenzo, Tlando, and Kyzatrex) utilize lipid-based self-emulsifying drug delivery systems that promote absorption via the intestinal lymphatic system into the thoracic duct. This mechanism bypasses initial portal circulation and hepatic first-pass metabolism. Historically, oral androgens relied on 17-alpha-alkylation (e.g., methyltestosterone) to survive hepatic first-pass metabolism, a chemical modification strongly associated with hepatotoxicity, cholestasis, and peliosis hepatis. Clinical trials and pharmacological reviews confirm that oral testosterone undecanoate avoids 17-alpha-alkylation and does not cause the classic liver toxicity associated with older oral androgens.

1:47:05Dereksupportedmoderate

Testosterone replacement therapy does not initiate de novo prostate cancer in men who are free of pre-existing prostate cancer cells.

"the actual impact on prostate-related issues and like growing cancer from scratch, if you don't have preexisting cancer cells, like you're not going to just like spawn cancer from taking testosterone. So I think that risk is a little bit overblown. Fortunately, we have data that seems to be pretty strongly indicating that you're not going to have to worry about that if you are somebody who is otherwise healthy, cancer-free" (said at 1:47:05)

Multiple systematic reviews and meta-analyses of randomized controlled trials (RCTs) evaluating testosterone replacement therapy (TRT) in hypogonadal men have found no statistically significant increase in the incidence of prostate cancer or clinically significant prostate cancer compared with placebo. Endogenous testosterone levels and exogenous replacement have not been shown to initiate de novo prostate cancer in men without pre-existing disease, supporting the saturation model of prostate androgen receptors, though researchers note that follow-up in most clinical trials is limited to short- and intermediate-term durations.

1:58:15Dereksupportedmoderate

Subcutaneous injection of testosterone provides slower absorption and more stable serum hormone concentrations compared to intramuscular injection.

"injecting subcutaneously into stomach fat or into any SubQ fat versus intramuscularly where it's more quickly going to get absorbed and assimilated. So you can also bleed out the effect even more and make it even more stable in your blood levels." (said at 1:58:15)

Comparative pharmacokinetic and clinical studies show that subcutaneous (SC) administration of testosterone esters results in a lower peak-to-trough fluctuation and avoids the rapid, supraphysiological spikes characteristically observed after intramuscular (IM) injections. In clinical comparisons and pharmacokinetic evaluations in hypogonadal men and individuals receiving gender-affirming hormone therapy, weekly SC injections deliver steady, therapeutic total and free testosterone concentrations over the dosing interval with lower post-injection peak levels compared to IM administration.

2:00:55Dereksupportedmoderate

Topical testosterone creams can accidentally transfer to children through skin or residue contact, causing secondary virilization.

"the cream, I guess I didn't mention the obvious, but like transference, if you have children, you have pets, like there are concerns with, you know, what you are going to rub it off on and like your hygiene with it. So that's worth mentioning cuz like there are cases of transference issues that have been noted in media. You know, I think I did a video a while ago where some dad accidentally was like wiping residue on his kid without even realizing it, even after he like thought he cleaned it, and his kid was like starting to get virilized from the from the testosterone residue" (said at 2:00:55)

Multiple published case reports and reviews document secondary transfer of topical testosterone gels/creams from adults to young children through skin contact or contaminated surfaces. Such accidental exposures have resulted in gonadotropin-independent precocious virilization in prepubertal children (including pubic hair growth, phallic/clitoral enlargement, accelerated linear growth, and elevated serum testosterone), which typically regresses or halts upon cessation of exposure.

2:06:00Dereksupportedhigh

Intratesticular testosterone is the primary mediator of spermatogenesis in the testes.

"So intratesticular testosterone is the significant mediator of spermatogenesis." (said at 2:06:00)

Intratesticular testosterone (ITT) is recognized in male reproductive endocrinology as the essential mediator for initiating and maintaining spermatogenesis. In the testis, local concentrations of testosterone are vastly higher than in circulating serum, acting on Sertoli cells and peritubular myoid cells to support germ cell maturation. Therapies that suppress endogenous LH production drastically deplete ITT, leading to impaired spermatogenesis and azoospermia, whereas maintaining or restoring ITT (for example, with human chorionic gonadotropin) preserves sperm production.

2:07:02Dereksupportedhigh

Exogenous testosterone suppresses the hypothalamic-pituitary-gonadal axis by inhibiting GnRH release from the hypothalamus and gonadotropins (LH and FSH) from the pituitary.

"So by that I mean the hypothalamus releases the GnRH, the gonadotropin-releasing hormone. So it's the hormone that causes the release of gonadotropins, hence the name. At the pituitary gland, the pituitary responds to that GnRH to then produce the gonadotropins, which are the luteinizing hormone LH and the FSH... So if you have exogenous testosterone, so like you're administering it yourself synthetically, you have basically told your brain, 'I have enough estrogen and testosterone via this injection I'm doing or whatever it is. So you cannot produce any more GnRH... As a result, we have no signal to produce pituitary hormones or the gonadotropins.'" (said at 2:07:02)

The speaker's explanation accurately reflects the established physiology of the hypothalamic-pituitary-gonadal (HPG) axis. Hypothalamic gonadotropin-releasing hormone (GnRH) stimulates pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Exogenous testosterone (acting directly or through its aromatized and 5alpha-reduced metabolites, estradiol and dihydrotestosterone) exerts negative feedback at both the hypothalamic and pituitary levels, suppressing GnRH release and reducing the secretion of LH and FSH.

2:07:33Dereksupportedhigh

In women, theca cells produce testosterone in the gonads, functioning analogously to Leydig cells in men.

"And women do too. It's just theca cells instead of, you know, Leydig cells." (said at 2:07:33)

In gonadal endocrinology, the 'two-cell, two-gonadotropin' model establishes that ovarian theca cells (specifically the theca interna) respond to luteinizing hormone (LH) by expressing CYP17A1 to synthesize androgens (androstenedione and testosterone), which are then converted to estrogens in adjacent granulosa cells by aromatase. This directly parallels testicular physiology, where Leydig cells respond to LH to synthesize androgens, making theca cells the ovarian functional analogue of testicular Leydig cells.

2:07:33Dereksupportedhigh

Sertoli cells support spermatogenesis and are regulated by follicle-stimulating hormone (FSH).

"And that intratesticular testosterone mediates spermatogenesis in unison with the Sertoli cells which are also supported by follicle-stimulating hormone." (said at 2:07:33)

The speaker's assertion accurately reflects standard male reproductive physiology. Spermatogenesis relies on the synergistic actions of intratesticular testosterone and follicle-stimulating hormone (FSH) acting directly on Sertoli cells, which provide structural and nutritional support to developing germ cells.

2:09:37Dereksupportedmoderate

Co-administration of hCG and recombinant FSH during testosterone therapy maintains testicular size, function, and spermatogenesis.

"like you can maintain everything while you're on testosterone via that manual signaling of hCG plus recombinant FSH. That's like the combo that basically replicates what would otherwise be the LH and FSH from your pituitary to your testes. You maintain structural the size, the functionality, sperm production, etc." (said at 2:09:37)

Exogenous testosterone therapy suppresses the hypothalamic-pituitary-gonadal (HPG) axis via negative feedback, shutting down endogenous luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion, which causes testicular atrophy, loss of intratesticular testosterone, and impaired spermatogenesis. Human chorionic gonadotropin (hCG) acts as an LH analogue on Leydig cells to preserve intratesticular testosterone and testicular volume, while FSH (including recombinant FSH) acts on Sertoli cells to stimulate and maintain sperm production. Clinical studies and reviews confirm that co-administering gonadotropins (hCG with or without FSH) during or alongside testosterone therapy can preserve testicular function, size, and spermatogenesis despite pituitary suppression.

2:10:08Dereksupportedhigh

Commercial human chorionic gonadotropin (hCG) is purified from the urine of pregnant women.

"Some people get highly estrogenic from hCG in particular, which is like literally in pregnant women's urine to stimulate Leydig cells. That's what it's purified from." (said at 2:10:08)

Commercial human chorionic gonadotropin (u-hCG) is purified from the urine of pregnant women, which contains high levels of the hormone secreted by placenta tissue. hCG binds to luteinizing hormone/hCG receptors on testicular Leydig cells to stimulate testosterone production (which can subsequently convert into estrogens). While recombinant hCG (r-hCG) produced via cell culture has also become available in recent decades, urinary extraction from pregnant women remains a major source for commercial hCG preparations.

2:13:45Dereksupportedhigh

Suppression of gonadotropins occurs within days of starting exogenous testosterone administration.

"it's pretty quick because like the suppression of the gonadotropins happens like within days. Like once you start to inject that hormone, like you've introduced an amount that is going to tell your brain, 'We have enough, don't make anymore.'" (said at 2:13:45)

Exogenous testosterone administration rapidly exerts negative feedback on the hypothalamic-pituitary-gonadal axis, suppressing the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Clinical trials evaluating intramuscular testosterone injections (such as testosterone enanthate) show significant suppression of both LH and FSH measured within days (e.g., at day 4 post-injection) across various doses.

2:17:26Dereksupportedhigh

Inulin clearance is the gold standard method for measuring glomerular filtration rate.

"an SDMA which is like a symmetric—it's another marker, more progressive marker for kidney function that is a proxy for inulin clearance with relative accuracy, which is like the gold standard of actual GFR for kidney filtration capacity." (said at 2:17:26)

Inulin clearance is widely established in physiology and nephrology as the reference gold standard for directly measuring glomerular filtration rate (mGFR). Because inulin is freely filtered at the glomerulus and neither reabsorbed, secreted, synthesized, nor metabolized by the renal tubules, its renal clearance accurately reflects GFR. While practical limitations (continuous intravenous infusion, timed urine collections, and assay complexity) have led to the routine clinical use of alternative markers (such as iohexol, 51Cr-EDTA, or estimated GFR equations), urinary inulin clearance remains the recognized gold standard benchmark.

2:17:58Dereksupportedhigh

Cystatin C-based estimated GFR is not influenced by muscle mass or creatine intake, unlike creatinine-based eGFR.

"one is more of like a kidney marker that is equivalent or slightly better than cystatin C estimated GFR, which is not influenced by muscle mass, creatine intake, or the array of things that can cause transient complete like to the point of it being unusable changes in the marker." (said at 2:17:58)

Serum creatinine is a metabolic byproduct of muscle creatine breakdown, making creatinine-based estimated glomerular filtration rate (eGFR) susceptible to variations in skeletal muscle mass, dietary protein, and creatine supplementation. In contrast, cystatin C is a low-molecular-weight protein produced at a relatively constant rate by all nucleated cells and filtered freely by the glomerulus. As confirmed by clinical nephrology guidelines and comparative biomarker studies, cystatin C-based eGFR is independent of creatine supplementation and muscle mass, providing an accurate alternative when creatinine-based estimates are confounded by body composition or dietary intake.

2:19:31Dereksupportedhigh

Exogenous androgens suppress sex hormone-binding globulin (SHBG) levels in a dose-dependent manner.

"SHBG will get suppressed dramatically by exogenous androgens in a dose-dependent manner. So it's not uncommon to see with bodybuilders who are using full-blown steroid cycles, SHBG levels in the single digits" (said at 2:19:31)

Randomized controlled trials and observational studies in athletes demonstrate that exogenous androgens and androgen receptor agonists suppress sex hormone-binding globulin (SHBG) levels in a dose-dependent manner. Hepatic production of SHBG is strongly down-regulated by androgenic activity, leading to substantial reductions during exogenous androgen administration and resulting in markedly suppressed, low or single-digit SHBG levels during high-dose anabolic-androgenic steroid cycles.

2:20:32Dereksupportedhigh

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the gold standard assay for measuring total testosterone.

"the gold standard for total testosterone is liquid chromatography with tandem mass spectrometry. If you use an immunoassay test, which is like the cheaper version, often it will be relatively inaccurate, especially at lower like more low levels" (said at 2:20:32)

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is widely recognized as the gold standard analytical method for measuring total testosterone due to its superior analytical specificity, sensitivity, and reliability compared to direct immunoassays. Immunoassays frequently suffer from cross-reactivity with other circulating steroids and matrix effects, resulting in significant inaccuracy and poor reproducibility, particularly at lower concentrations (such as in women, children, and hypogonadal or castrated men).

2:21:03Dereksupportedhigh

Equilibrium dialysis and equilibrium ultrafiltration are direct measurement assays for free testosterone rather than calculated estimates.

"And for free testosterone, you don't want to be using a calculation. Ideally, you would want to be measuring through equilibrium ultrafiltration or equilibrium dialysis, which are like actual measurements, not estimates based on calculations." (said at 2:21:03)

Equilibrium dialysis (ED) and equilibrium ultrafiltration (UF)—often followed by mass spectrometry (e.g., LC-MS/MS)—are physical separation reference methods that directly quantify the unbound (free) testosterone fraction in serum water. In clinical chemistry, these direct measurement assays serve as the gold-standard reference methods against which calculated free testosterone estimates (such as the Vermeulen or Ly equations based on total testosterone, SHBG, and albumin) and direct analogue immunoassays are evaluated.

2:23:06Dereksupportedmoderate

Androgens suppress lipoprotein(a) [Lp(a)] levels.

"Lp(a) at baseline. Especially because androgens suppress Lp(a) uniquely, which a lot of people don't realize is affected by androgens" (said at 2:23:06)

Randomized controlled trials and clinical evidence demonstrate that androgen administration (including testosterone replacement therapy and synthetic steroids with androgenic activity) leads to a reduction or suppression of circulating lipoprotein(a) [Lp(a)] concentrations.

2:26:44Dereksupportedhigh

Oral contraceptives artificially suppress testosterone levels in women.

"And then yeah, the oral contraceptives is significant and worth noting. If you're on that, like you almost certainly are artificially suppressing yourself into like the equivalent of hypo territory for women." (said at 2:26:44)

Combined oral contraceptives (COCs) significantly suppress circulating testosterone levels in healthy women. A systematic review and meta-analysis of 42 experimental studies comprising 1,495 healthy women (aged 18–40 years) demonstrated that COC use substantially decreases both total testosterone (mean difference: -0.49 nmol/L) and free testosterone (a mean relative decrease of 61%), while significantly increasing sex hormone-binding globulin (SHBG) levels (mean increase: 99.08 nmol/L). This suppression occurs across different types of progestins and estrogen dosages via inhibition of ovarian and adrenal androgen production alongside elevated SHBG binding.

2:28:16Dereksupportedhigh

There are no FDA-approved testosterone medications specifically for women in the United States.

"there's no FDA-approved medication for women for testosterone in the US. There is in Australia apparently" (said at 2:28:16)

The speaker's statement is accurate. Currently, there are no testosterone formulations or medications approved by the United States Food and Drug Administration (FDA) specifically indicated for women. Women in the U.S. who receive testosterone therapy are prescribed off-label treatments using lower doses of FDA-approved male formulations or off-label compounded preparations. In contrast, Australia's regulatory authority (the Therapeutic Goods Administration, TGA) has approved a female-specific transdermal testosterone cream (AndroFeme 1) for the treatment of hypoactive sexual desire disorder in postmenopausal women.

2:28:46Dereksupportedmoderate

Voice deepening in women caused by androgen/testosterone virilization is irreversible.

"For women, if you get irreversible voice deepening, like that is quality-of-life destroying for some of them and you can't just fix it." (said at 2:28:46)

Voice deepening resulting from androgen or testosterone exposure in women is recognized as an irreversible virilizing effect. Androgens promote hypertrophy of the laryngeal musculature and vocal fold tissues, lowering the fundamental frequency (pitch). Once structural changes occur, stopping androgen therapy or removing the androgen-producing source does not restore the original pitch, often requiring voice therapy or surgical intervention (such as Wendler glottoplasty) to raise vocal frequency. Systematic and scoping reviews confirm that androgen-induced dysphonia and pitch lowering can permanently alter female vocal function and negatively impact quality of life.

2:32:24Dereksupportedhigh

In women, a substantial portion of testosterone is produced by adrenal synthesis and peripheral tissue conversion rather than solely by the ovaries.

"Like a lot of the testosterone is mediated through adrenal synthesis and peripheral tissue conversion. It's not all ovarian." (said at 2:32:24)

Circulating testosterone in healthy women is derived from three primary sources: ovarian secretion, adrenal secretion, and the peripheral conversion of pro-androgen precursors (such as androstenedione and DHEA). Endocrine literature establishes that direct ovarian secretion accounts for only approximately 25% of total testosterone production in reproductive-aged women, with approximately 25% secreted directly by the adrenal glands and roughly 50% arising from peripheral conversion in target tissues.

2:18:55Dereksupportedhigh

Exogenous testosterone and androgen administration lowers and suppresses HDL cholesterol levels.

"I think the lipid panel, definitely a baseline HDL to see how much it gets lowered by the dose of testosterone you're using because you will likely see a suppression if you are elevating your testosterone beyond what you are at." (said at 2:18:55)

Extensive clinical trial data and meta-analyses of randomized controlled trials demonstrate that exogenous testosterone administration lowers and suppresses serum HDL cholesterol levels. The magnitude of HDL suppression is dose-dependent, with higher doses or elevated baseline testosterone levels producing more pronounced decreases in HDL cholesterol.

2:17:20Dereksupportedmoderate

Symmetric dimethylarginine (SDMA) serves as a biomarker for kidney filtration capacity and inulin clearance.

"an SDMA which is like a symmetric—it's another marker, more progressive marker for kidney function that is a proxy for inulin clearance with relative accuracy, which is like the gold standard of actual GFR for kidney filtration capacity." (said at 2:17:20)

Symmetric dimethylarginine (SDMA) serves as an endogenous circulating marker of renal function and glomerular filtration rate (GFR). A systematic review and meta-analysis of 18 studies evaluating 2,136 patients demonstrated that systemic SDMA concentrations correlate strongly with inulin clearance (R = 0.85, 95% CI 0.76–0.91, P < 0.0001), as well as with other clearance methods and serum creatinine.

2:34:25Dereksupportedhigh

DHEA supplementation does not meaningfully impact men's testosterone levels because the vast majority of male testosterone is produced intratesticularly.

"DHEA. I'm sure at some point we would have ended up talking about—not meaningfully impactful for men's testosterone levels because the majority is driven through intratesticular testosterone production." (said at 2:34:25)

The speaker's claim consists of two linked assertions: 1) that DHEA supplementation does not meaningfully impact men's testosterone levels, and 2) that this is because male testosterone is predominantly driven by intratesticular production. This is supported by high-certainty evidence. A comprehensive meta-analysis of randomized clinical trials (Ahmadi et al., 2020) demonstrated that while DHEA supplementation raises testosterone significantly in women (WMD: 30.98 ng/dL), its effect in men is minimal/substantially smaller (WMD: 21.36 ng/dL; and in men >60 years or with androgen deficiency, increments are minor). Male testosterone production occurs predominantly (over 95%) in the Leydig cells of the testes via intratesticular steroidogenesis driven by LH, whereas adrenal DHEA conversion contributes minimally to circulating total testosterone levels in males.

2:34:40Dereksupportedhigh

In women, a significant portion of circulating testosterone is derived from DHEA conversion.

"But for women, because you only have such a small amount, it's like, you know, 15 to 70 total, a significant chunk of that could be driven through DHEA-mediated conversion." (said at 2:34:40)

In women, total testosterone concentrations are substantially lower than in men (typically ~15–70 ng/dL), and a significant portion of circulating testosterone is not secreted directly by the gonads but arises from the peripheral conversion of adrenal and ovarian precursor pro-androgens, primarily dehydroepiandrosterone (DHEA/DHEA-S) and androstenedione.

2:35:25Dereksupportedhigh

Oral DHEA supplementation can fully attenuate the testosterone suppression induced by combined oral contraceptives in women.

"Like I've seen pretty dramatic changes to the degree of women on combined oral contraceptives attenuating entirely the loss in testosterone production via the progestin- and estrogen-induced suppression through the DHEA." (said at 2:35:25)

The claim is supported by clinical trial evidence. In a randomized, double-blind, placebo-controlled crossover study of 81 women using combined oral contraceptives (containing ethinyl estradiol combined with either levonorgestrel or drospirenone), co-administration of 50 mg/day of oral DHEA fully restored circulating free testosterone levels back to pre-contraceptive baseline values in both contraceptive formulations, as well as normalizing total testosterone levels.

2:36:00Dereksupportedhigh

Studies investigating DHEA supplementation typically use doses between 25 and 50 milligrams.

"25 to 50 would be like what you see in the studies" (said at 2:36:00)

Clinical trials and meta-analyses examining oral dehydroepiandrosterone (DHEA) supplementation in adults and postmenopausal women standardly utilize daily dosages of 25 mg to 50 mg to restore physiological hormone levels or evaluate metabolic and endocrine outcomes.

2:38:50Dereksupportedhigh

The scalp skin has a high density and expression of 5-alpha reductase enzymes that locally convert testosterone to dihydrotestosterone (DHT).

"And in particular in the skin, in the scalp especially too, you will have—there's way more 5-alpha reductase density in men for converting testosterone to DHT." (said at 2:38:50)

Human scalp skin and hair follicles express 5-alpha reductase enzymes (specifically type 1 and type 2 5-alpha reductase), which locally convert circulating testosterone into dihydrotestosterone (DHT). This local conversion in scalp dermal papilla cells is well-documented and forms the physiological basis for androgenetic alopecia as well as therapeutic 5-alpha reductase inhibitors like finasteride.

2:41:00Dereksupportedhigh

Androgenetic alopecia involves androgen-induced miniaturization of the hair follicle and a progressive shortening of the anagen growth phase.

"So like the net result is the follicle literally like starves itself and miniaturizes. Like the follicle becomes weaker, thinner, and over time the anagen phase, which is like the growth phase of the hair follicle, shortens, shortens, shortens" (said at 2:41:00)

The speaker's statement accurately describes the established pathophysiological hallmark of androgenetic alopecia. In genetically predisposed hair follicles, androgen signalling (primarily via dihydrotestosterone interacting with androgen receptors in dermal papilla cells) causes progressive follicle miniaturization and a step-wise shortening of the anagen (active growth) phase over repeated hair cycles.

2:41:45Dereksupportedhigh

Hair follicles transplanted from areas not prone to androgenetic alopecia retain their resistance to androgen-mediated miniaturization when moved to balding areas.

"And it's really interesting too cuz these hair follicles, they're not prone to the same miniaturization. So like even if you transplant it from here to here, like it's not going to undergo the same effect even though it's like in that area" (said at 2:41:45)

The speaker accurately describes the foundational biological principle of hair transplantation known as 'donor dominance,' originally established by Norman Orentreich in 1959. Under this principle, hair follicles harvested from regions resistant to androgenetic alopecia (such as the occipital safe donor area) retain their intrinsic genetic resistance to androgen-mediated miniaturization and continue to grow normally when transplanted into androgen-sensitive balding recipient sites.

2:44:45Dereksupportedmoderate

Individuals with congenital 5-alpha reductase deficiency have normal testosterone production and normal muscle mass, but experience impaired genital development, reduced facial hair, and no temporal hairline recession.

"they found that individuals that had a mutation in the gene that encodes for 5-alpha reductase seem to not undergo full sexual maturation in adolescence, and they would end up with, shockingly, the same amount of muscle mass as like, you know, their—like, for example, siblings who weren't affected, but inhibited maturation of genitals, for example... but also no facial hair growth really, and no temporal recession" (said at 2:44:45)

Classic clinical descriptions of individuals with congenital steroid 5-alpha-reductase deficiency demonstrate that while testosterone levels rise normally during puberty—leading to normal muscle mass development, voice deepening, and virilization—the impaired conversion of testosterone to dihydrotestosterone (DHT) results in ambiguous or underdeveloped external genitalia at birth, absent or substantially decreased facial/body hair, and an absence of temporal hairline recession or male-pattern baldness.

2:49:50Dereksupportedhigh

Inhibiting DHT via 5-alpha reductase inhibitors can mildly suppress male fertility metrics because intratesticular DHT contributes to spermatogenesis.

"Like it will also—not dramatically, but could suppress fertility metrics mildly because intratesticular androgenic signaling does dictate spermatogenesis, that includes DHT. So like if you're reducing the DHT a lot, that might impede your fertility to some extent too" (said at 2:49:50)

Randomized controlled trial data indicate that 5-alpha reductase inhibitors (such as finasteride and dutasteride), which significantly suppress dihydrotestosterone (DHT) levels, cause modest and generally reversible decreases in semen parameters. A double-blind, placebo-controlled trial in 99 healthy men demonstrated that 1 year of daily treatment with dutasteride (0.5 mg) or finasteride (5 mg) caused mild reductions in total sperm count, semen volume, and sperm motility without altering sperm morphology.

2:53:15Dereksupportedlow

Ketoconazole shampoo acts as a mild anti-androgen and 5-alpha reductase inhibitor with studies showing hair growth results comparable to 2% minoxidil.

"Ketoconazole does help. There's studies showing it's equivalent to the hair growth results of 2% minoxidil via totally different mechanism, which is like very significant for something that's like an over-the-counter shampoo" (said at 2:53:15)

A comparative clinical study by Piérard-Franchimont et al. (1998) evaluated 2% ketoconazole shampoo against unmedicated shampoo with or without 2% minoxidil solution in men with androgenetic alopecia, finding that hair density, shaft diameter, and the proportion of anagen follicles improved almost similarly in both the ketoconazole and 2% minoxidil groups. Subsequent systematic reviews affirm that topical ketoconazole demonstrates therapeutic potential in androgenetic alopecia through anti-inflammatory and potential local anti-androgenic effects, though the overall body of evidence remains limited by small sample sizes and a need for larger randomized controlled trials.

2:54:10Dereksupportedhigh

Topical minoxidil requires conversion into minoxidil sulfate in the scalp by the sulfotransferase enzyme to exert its hair growth stimulating effect.

"So it needs to convert into minoxidil sulfate in the scalp to actually work. And if you have inadequate sulfotransferase enzyme activity, it will not—you could be a total non-responder even though you're using the full drug dose every day." (said at 2:54:10)

The claim is supported. Topical minoxidil functions as a prodrug that must be sulfated into its active metabolite, minoxidil sulfate, by sulfotransferase enzymes (specifically SULT1A1) located in the outer root sheath of hair follicles in the scalp. Interindividual differences in follicular sulfotransferase enzymatic activity strongly correlate with treatment response, and low or absent enzyme activity in the scalp accounts for non-responsiveness to topical therapy.

2:55:00Dereksupportedmoderate

Compounding topical minoxidil with tretinoin upregulates sulfotransferase enzyme activity in the scalp, improving minoxidil conversion.

"One is compounding the minoxidil with tretinoin, which can upregulate the sulfotransferase enzyme and allow more of that conversion to take place." (said at 2:55:00)

Clinical research demonstrates that topical tretinoin application upregulates follicular sulfotransferase enzyme activity in the scalp, increasing the enzymatic conversion of minoxidil into its active form (minoxidil sulfate). In clinical testing, 5 days of topical tretinoin application increased sulfotransferase expression and converted 43% of predicted minoxidil non-responders into responders.

2:57:54Dereksupportedhigh

Minoxidil functions as a potassium channel opener and when taken orally can cause pericardial effusion, water retention, and electrolyte dysregulation.

"like pericardial effusion, like water retention, dysregulation of electrolyte balance—like it's a potassium channel opener, that's how it works. And systemically it has a much more significant side effect profile than topically." (said at 2:57:54)

Minoxidil is an ATP-sensitive potassium channel opener that causes vascular smooth muscle relaxation. Oral administration is well established to cause sodium and fluid retention, altered renal electrolyte handling (via stimulation of electrolyte and fluid reabsorption in the loop of Henle and activation of the renin-angiotensin-aldosterone axis), and, in rare or severe cases, pericardial effusion. Consequently, systemic (oral) administration carries a substantially greater adverse effect profile compared to topical application.

3:02:05Dereksupportedmoderate

Studies have shown that combining microneedling with topical minoxidil can produce up to four times greater hair regrowth results compared to minoxidil alone.

"It seems more like it's probably ensuring you're actually getting this to where it was supposed to go to begin with, but maybe wasn't getting fully assimilated, which is fine if that's what it does. It's just like that's what some people need in order to get the absorption, but it could be the difference of 4x the results I've seen in some studies." (said at 3:02:05)

Published randomized clinical trials support the claim. In a seminal 2013 randomized, evaluator-blinded trial of 100 men with androgenetic alopecia (Dhurat et al.), patients receiving weekly microneedling plus 5% topical minoxidil experienced a mean hair count increase of 91.4 hairs/cm² at 12 weeks, compared to 22.2 hairs/cm² in the minoxidil-alone group—an increase of approximately 4.1 times. Subsequent systematic reviews and meta-analyses have consistently confirmed that combining microneedling with topical minoxidil yields significantly greater improvements in hair count and density than minoxidil monotherapy.

3:03:04Dereksupportedmoderate

5-alpha reductase inhibitors reduce the synthesis of allopregnanolone, which decreases GABAergic neurosteroid signaling.

"Potentially through the balance of neurotransmitters, anxiolytic versus—there's a whole rabbit hole to go down of inhibition of allopregnanolone, which is thought to be the main thing implicated in postpartum depression being deprived of it... And seemingly by inhibiting 5-alpha reductase, you may be inhibiting that GABAergic signaling through that anxiolytic, calming molecule essentially" (said at 3:03:04)

The speaker's statement is supported by pharmacological and biochemical evidence. 5-alpha reductase is the key enzyme responsible for converting progesterone into 5α-dihydroprogesterone, which is subsequently converted into allopregnanolone. Research shows that 5-alpha reductase inhibitors such as finasteride block this pathway, markedly reducing brain levels of allopregnanolone. Because allopregnanolone is a potent positive allosteric modulator of GABA_A receptors that exerts anxiolytic and calming effects, inhibiting its synthesis decreases GABAergic neurosteroid signaling. Furthermore, allopregnanolone deficiency is implicated in postpartum depression, where allopregnanolone therapy (brexanolone) is approved for clinical treatment.

2:45:00Dereksupportedmoderate

The human scalp contains approximately 70,000 to 100,000 hair follicles on average.

"like you have on average, depending on the ethnicity, but like I think it's like 70 to like 80,000, upwards of 100,000 hair follicles on your head." (said at 2:45:00)

Morphometric and histopathological studies of the human scalp demonstrate that the total number of scalp hair follicles and hairs typically falls within the range of approximately 70,000 to 100,000 or more, with established variations across different ethnic backgrounds. Scalp surface area in adults averages approximately 490 to 500 cm², and standard 4-mm punch biopsies across various populations (such as Caucasian, Asian, and Hispanic cohorts) typically report mean follicular counts of 20 to 28 per biopsy (roughly 160 to 225 follicles/cm²), yielding total scalp hair follicle estimates in line with the stated range.

2:48:00Dereksupportedhigh

Dutasteride administration results in near-complete inhibition of systemic DHT levels.

"dutasteride has a similar side effect profile to finasteride even in studies comparing them where you have near full inhibition of systemic DHT versus only 60 to 70% via finasteride" (said at 2:48:00)

Randomized controlled trials directly comparing dutasteride and finasteride confirm that dutasteride results in near-complete systemic dihydrotestosterone (DHT) suppression (approximately 94% to 98% reduction at standard clinical doses of 0.5 mg to 5.0 mg daily) due to dual inhibition of both type 1 and type 2 5-alpha-reductase isoenzymes. In contrast, selective type 2 inhibition with finasteride suppresses serum DHT by approximately 70% to 73%.

2:59:30Dereksupportedmoderate

Recent research indicates that microneedling at a depth of 0.6 mm is potentially as effective for hair loss as a 1.5 mm depth.

"And newest literature reveals that you might be able to get away with only doing a 0.6 mm depth as opposed to the old studies had everyone doing 1.5, which was guaranteed to draw blood." (said at 2:59:30)

Published clinical evidence supports the claim that shallower microneedling depths (around 0.6 mm) are effective for androgenetic alopecia and can achieve outcomes comparable to or better than deeper penetration. While early microneedling protocols for hair loss frequently utilized 1.5 mm depths designed to produce pinpoint bleeding, a randomized clinical trial comparing 0.6 mm and 1.2 mm depths alongside topical minoxidil found that the 0.6 mm depth produced significant improvements in hair count and thickness over minoxidil alone, and tended to be more beneficial than deeper penetration.

3:03:04Dereksupportedhigh

A pharmaceutical was developed to treat postpartum depression by restoring allopregnanolone signaling.

"inhibition of allopregnanolone, which is thought to be the main thing implicated in postpartum depression being deprived of it. And there's a literal pharmaceutical that was developed to manually restore that in women that just had birth and have postpartum depression." (said at 3:03:04)

The claim is accurate. Brexanolone is an FDA-approved medication developed specifically for postpartum depression (PPD). It is an intravenous formulation of allopregnanolone, an endogenous neurosteroid that acts as a positive allosteric modulator at GABAA receptors. The rapid drop in allopregnanolone levels following childbirth is thought to trigger depressive episodes in susceptible women, and brexanolone was developed to directly restore allopregnanolone signaling. In addition, an oral synthetic neuroactive steroid analogue acting on the same pathway, zuranolone, was also developed and approved for PPD.

3:04:35Rhonda Patrick (host)supportedmoderate

23andMe measures specific single nucleotide polymorphisms (SNPs) associated with susceptibility to placebo and nocebo effects.

"there's SNPs that are known that you can look at, and even 23andMe does measure these SNPs for placebo versus nocebo." (said at 3:04:35)

Research has identified several candidate single nucleotide polymorphisms (SNPs)—collectively termed the 'placebome'—associated with individual differences in placebo and nocebo responses. Key documented variants include polymorphisms in the catechol-O-methyltransferase (COMT rs4680), mu-opioid receptor (OPRM1 rs1799971), and fatty acid amide hydrolase (FAAH rs324420) genes, which influence dopaminergic, opioid, and endocannabinoid neurotransmission during placebo analgesia. Standard commercial genotyping microarrays (such as those used by 23andMe) include probes for these common candidate SNPs in raw genetic data files, although 23andMe does not offer a dedicated health or trait interpretation report for placebo responsiveness.

3:05:05Dereksupportedhigh

Minoxidil acts as a hair growth stimulant but does not attenuate or prevent hair follicle miniaturization caused by DHT.

"clarifying quick on minoxidil, though: it's a growth stimulant. It does absolutely nothing that we know of to attenuate the miniaturization caused by DHT." (said at 3:05:05)

Minoxidil is well established in the dermatological and pharmacological literature as a non-hormonal hair growth stimulant (acting primarily via potassium channel opening, microvascular dilation, and promotion of follicular cell survival and anagen phase lengthening). It possesses no intrinsic 5-alpha reductase inhibitory or androgen receptor antagonist activity and does not directly block or attenuate the hormonal cascade through which dihydrotestosterone (DHT) drives progressive hair follicle miniaturization.

3:08:11Dereksupportedhigh

Graded dose-response studies using dutasteride alongside testosterone showed that suppressing DHT had no effect on strength or muscular hypertrophy.

"Graded dose-response studies using dutasteride alongside testosterone, even at supra dosages, the dutasteride getting wiped out had no impact whatsoever on strength and muscular hypertrophy." (said at 3:08:11)

A double-blind randomized controlled trial (Bhasin et al., JAMA 2012) evaluated 139 healthy men receiving graded doses of testosterone enanthate (50, 125, 300, or 600 mg/week) for 20 weeks alongside either placebo or 2.5 mg/day of the dual 5α-reductase inhibitor dutasteride (to suppress DHT). Suppression of DHT conversion by dutasteride resulted in no significant differences in gains in fat-free mass or muscle strength across all dose tiers (including supraphysiologic doses), confirming that 5α-reduction to DHT is not required for testosterone-mediated muscle hypertrophy or strength increases.

  • supports: Effect of testosterone supplementation with and without a dual 5α-reductase inhibitor on f… (JAMA 2012) · cited 153x in the literature
    "The dose-adjusted differences between the dutasteride and placebo groups for fat-free mass were not significant (P = .18). Changes in fat mass, muscle strength, sexual function, prostate volume, sebum production, and hematocrit and lipid levels did not differ between groups. Conclusions: Changes in fat-free mass in response to graded testosterone doses did not differ in men in whom DHT was suppressed by dutasteride from those treated with placebo, indicating that conversion of testosterone to DHT is not essential for mediating its anabolic effects on muscle." (abstract, results and conclusions, passage verified)
    pubmedfull study (doi)
3:07:41Dereksupportedhigh

Dihydrotestosterone (DHT) is the most potent androgenic hormone in the human body.

"DHT is literally the most androgenic hormone in your body." (said at 3:07:41)

Dihydrotestosterone (5α-DHT) is widely established in endocrinology as the most potent endogenous androgen in the human body. It is synthesized primarily from testosterone by 5α-reductase enzymes and possesses significantly higher affinity for the androgen receptor (as well as a slower dissociation rate) compared to testosterone and other endogenous androgens.

Unverified means no publication matching the claim was located; it does not prove the claim false. Spotted an error? See the corrections policy - disputes from the people quoted are prioritized.