Testosterone is the primary androgen in men and has important anabolic roles in women. Normal endogenous production in men is on the order of a few milligrams per day.

Testosterone
Testosterone
Abbreviation T
Molecular formula C₁₉H₂₈O₂
Type Steroid hormone (androgen)
Administration Topical (oil/cream, preferred), oral (in oil), injection (caution with esters)
Bioavailability Topical: good; oral in oil: workable; injections: high but solvent/ester concerns
Synonyms 17β-Hydroxyandrost-4-en-3-one
Source Testes (men), ovaries/adrenals (women); from cholesterol → Pregnenolone → DHEA pathway
Ray's verdict Depends on context
Supportive at physiological doses; skeptical of TRT megadosing; aromatizes to Estrogen.

Physiological androgen levels are supportive; megadose TRT protocols that ignore upstream metabolism are approached skeptically. Low testosterone often tracks low Thyroid, high Estrogen, excess PUFA, and chronic Stress rather than isolated testicular failure.[1]

Dosing

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See Anabolic steroids for supraphysiological use and its harms. Prescription TRT decisions belong with a clinician and laboratory monitoring.

History

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Etymology

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The name combines "testis" (the gland that produces it) with "sterol" and the ketone suffix "-one."

Ernst Laqueur's group isolated testosterone from bull testicles in 1935. That same year, Adolf Butenandt and Leopold Ruzicka independently synthesized it from cholesterol, work for which they shared the 1939 Nobel Prize in Chemistry.

Aromatization and estrogen

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Testosterone is converted to estrogen in the testicle itself, a conversion held back by the hormonal environment of youth, while declining T3 with age lowers pregnenolone production.[2]

Testosterone aromatizes to Estrogen (estradiol). Free PUFA in circulation can increase estrogen activity by displacing estradiol from sex-hormone-binding globulin, making more estrogen biologically available.[1]

Deficiency of testosterone causes vascular leakage into the prostate.

— Ray Peat[3]

Stress and male fertility

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In prospective military cohort data, testosterone buffered cortisol-linked PTSD risk: cortisol predicted worse outcomes when testosterone was low. Testosterone and cortisol regulate stress reactivity reciprocally.[4] Two weeks of added sugar (~450 g/day on top of a healthy baseline diet) normalized poor sperm motility in all young men who started below reference range, with rapid shifts in sperm small-RNA profiles.[5] Retinoic acid receptor-α antagonism or dietary vitamin A deficiency produces male sterility by the same pathway used clinically to reversibly suppress spermatogenesis at low milligram-per-kilogram doses.[6] Hindlimb unloading (disuse stress) in rats for 30 days raised corticosterone, estradiol, and prolactin, lowered testosterone, gonadotropins and intratesticular DHT, and worsened all semen measures.[7]

Fasting and testicular steroids

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Four days of fasting in rats raises testicular corticosterone, suppresses side-chain cleavage and 3β-HSD, and reduces intratesticular testosterone roughly 98% despite only modest changes in serum testosterone.[8]

Endotoxin and testicular steroids

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In a placebo-controlled trial, one small intravenous dose of bacterial endotoxin given to healthy lean young men caused a short burst of inflammation, and their testosterone fell by about 30% within hours before returning to normal the next day.[9] LH and FSH, the pituitary signals that drive the testes, did not change, which places the drop in the testes rather than the brain.[9] In the same paper, fertility-clinic men with higher blood markers of endotoxin exposure had lower testosterone, though the link was weak, and the study did not show that the endotoxin came from the gut.[9]

In mice, a large endotoxin injection cut testosterone within two hours, together with a sharp loss of the protein that carries cholesterol into the mitochondria where testosterone synthesis starts; the enzymes further down the pathway fell later, and testosterone stayed low for days.[10] In castrated male rats, an endotoxin injection cut the number and size of LH pulses and lowered FSH.[11] In mice given a single high dose, testosterone and the testicular genes for steroid-making enzymes fell, but blood LH and FSH rose instead of falling.[12]

If you keep a stream of good clean material moving through, you can lower the toxins that should be excreted. That would include unwanted hormones, including estrogen, which the liver should be able to eliminate 100%. It will reduce the endotoxin and shift the serotonin and histamine such that it will also lower cortisol production. That total pattern will increase the good hormones, like progesterone and testosterone.

— Ray Peat[13]

Intratesticular steroids in infertile men

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Across 24 fertile and 18 infertile men, testosterone was similar in plasma and in testicular tissue; infertile men instead showed lower intratesticular pregnenolone, androstenedione, and DHT, with higher plasma DHT, so peripheral testosterone alone did not mark the tissue steroid differences.[14] In NOA versus OA, serum testosterone/estradiol likewise did not correlate with ITT/ITE2; higher Leydig-cell aromatase intensity went with lower ITT, higher ITE2, and a lower ITT/ITE2 ratio (about 42,590 to 25,774; 3,177 to 5,856; 15.7 to 4.6).[15] See Aromatase and Fertility.

DHT and pancreatic beta cells

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DHT protects insulin-secreting INS-1 cells from oxidative senescence and may represent a senolytic strategy for type 2 diabetes prevention.[16]

DHT and morphogenesis

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In rats, ETU-induced severe hypothyroidism aligned with reduced DHT despite higher testosterone, supporting that 5α-reductase blockade can mimic hypothyroid androgen profiles seen in post-finasteride syndrome.[17] Pharmaceutical 5α-reductase inhibitors (finasteride, dutasteride) dose-dependently disrupt gastropod shell coiling during embryogenesis, indicating a conserved morphogenetic role for DHT-pathway steroids beyond androgen-receptor signaling.[18]

Prostate inflammation and androgen deprivation

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Prostate cancer risk is unrelated to serum androgen concentrations in the saturation model: high testosterone does not predispose, and low testosterone is not protective; the disease appears as men age and testosterone declines, not in youth at peak levels.[19] In Noble rats, testosterone plus estradiol for 16 weeks induced dorsolateral prostate dysplasia in all animals; androgen alone did not.[20]

Androgen receptor activation decreased proliferation in thyroid cancer cell lines and downregulated PD-L1 (an immune-evasion checkpoint protein) in thyroid cancer, two independent mechanisms by which androgen/DHT signaling may suppress rather than promote thyroid cancer growth.[21][22]

Microbial metabolites of the steroid drostanolone enanthate were more toxic than the parent compound to cervical (HeLa) and prostate (PC-3) cancer cell lines in vitro.[23] Deleting the androgen receptor in prostate luminal cells disrupted tight junctions, leaked inflammatory cytokines, recruited immune cells, and promoted epithelial proliferation in a self-amplifying inflammatory cycle.[24]

Intermittent (not continuous) DHT administration enhanced the cytotoxic effect of docetaxel chemotherapy in a prostate-cancer xenograft model, via modulation of ERβ, androgen receptor, and NEK2. In the bipolar-androgen-therapy paradox, cycling high-dose androgen can suppress rather than promote prostate tumor growth, while estradiol strongly promotes it.[25]

Central androgen signaling and atherosclerosis

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Men studied months after myocardial infarction had persistently low urinary androgen metabolites including testosterone-derived 17-ketosteroids alongside elevated glucocorticoid activity.[26] Childhood poverty predicted shallower pubertal testosterone rises, smaller adolescent hippocampal growth, and worse emotion regulation and depression in both sexes.[27] Low-testosterone men randomized to testosterone or DHT gels showed androgen-driven improvements in insulin sensitivity; DHT achieved greater metabolic benefit at about one-quarter the absorbed dose.[28] Among men with normal testosterone, each 10% rise in DHT associated with roughly 4.7% fewer hypogonadism symptoms, emphasizing tissue DHT over circulating testosterone for androgenic function.[29] Six months of DHEA 50 mg daily reduced abdominal visceral fat about 7–10% and improved insulin sensitivity in elderly men and women in a randomized trial.[30] In vitro testing of fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine showed reduced testosterone, DHT, DHEA, and progesterone production from gonadal and adrenal tissue.[31] A cultured rat Leydig-cell study, not a human trial, found that serotonin stimulated CRF secretion up to 4-fold and inhibited basal and hCG-stimulated cAMP and testosterone production (ID50 1 nM) via 5-HT2 receptors; CRF antibody and alpha-helical CRF-(9-41) prevented the inhibitory action, and ketanserin blocked it.[32] Hospitalized men with COVID-19 who died had lower testosterone and higher estradiol-to-testosterone ratios predicting hyperinflammation and in-hospital mortality independent of comorbidities. Adolescent scoliosis patients showed lower serum androgen levels and impaired androgen-receptor control of chondrocyte IL-6, linking androgen deficiency to structural cartilage deformity.[33] Prostate tissue dihydrotestosterone was about 90% lower in recurrent prostate cancer than in benign disease, with one-third of cancer specimens showing undetectable DHT despite preserved testosterone.[34] Prospective data in women over 70 linked low circulating testosterone and DHEA (but not low estrone) to roughly doubled incidence of major cardiovascular events.[35] Androgen-receptor blockade by hydroxyflutamide or p,p′-DDE abolished dihydrotestosterone's protective effects against estrogen-driven breast-cancer cell proliferation in vitro.[36] Serum dihydrotestosterone was 61% lower in older men with higher carotid intima-media thickness, pulse-wave velocity, and inflammatory markers, correlating inversely with arterial stiffness indices.[37] Central dihydrotestosterone infusion in orchiectomized mice prevented mediobasal hypothalamic astrogliosis and reduced liver and leukocyte inflammatory signaling and monocytosis on a high-fat diet.[38]

Soda and androgen signaling

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Fifteen days of ad-libitum undiluted cola raised mouse testis weight, serum testosterone, and testicular androgen-receptor mRNA versus water controls.[39]

DHT in elderly men

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Intramuscular stanolone (DHT) 50 mg every other day in men over 70 improved nitrogen, potassium, and phosphorus retention on adequate or low-protein diets, increased 17-ketosteroid excretion, and restored libido and mood in long-stay geriatric patients.[40]

Androgen loss and Parkinson's disease

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In Wobbler mice modeling ALS, testosterone falls in testis, plasma, brain, and spinal cord while corticosterone rises; plasma steroid levels correlate with cervical spinal cord concentrations.[41] Castration in male mice raises nigral iNOS, lowers GDNF, and produces Parkinson-like motor deficits and dopamine neuron loss; DHT pellet replacement preserves tyrosine hydroxylase neurons, striatal dopamine, and motor performance.[42]

Male sexual function without estrogen

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Transdermal DHT for 24 months in eugonadal men suppressed serum testosterone, LH, FSH, and estradiol to castration-range levels without spontaneous complaints or discontinuations for adverse sexual effects; DHT changed none of 33 sexual-function and mood measures except a mild, reversible decrease in overall sexual desire, while age and BMI were the main predictors of sexual decline.[43] In separate trials, tamoxifen (raising endogenous testosterone without lowering estradiol), testolactone (~50% lower circulating estradiol), and DHT replacement in hypogonadal men did not impair established sexual function, supporting that aromatization to estrogen is not required to maintain male sexual function in adults with an established sex life.[44]

In a controlled feeding study, shifting men from a low-fat, high-fiber diet to a higher-fat, lower-fiber diet raised plasma and urinary androgens (including free testosterone), while the opposite shift lowered them, one of the earliest clean demonstrations that dietary fat/fiber composition, not just genetics, drives circulating androgen levels.[45]

Klotho (anti-aging gene)

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Androgens, especially DHT acting through the androgen receptor, directly increase expression of the anti-aging gene Klotho in the kidney, with AR shown to bind the klotho gene promoter directly; the effect is blocked by the AR antagonist flutamide.[46] Estrogen has the opposite effect, decreasing klotho expression, with more potent estrogens (e.g. synthetic ethinyl estradiol) suppressing it more than endogenous estradiol.[47] Klotho decline tracks with most major chronic diseases (diabetes, cardiovascular disease, cancer, neurological and mental-health conditions). Androgen/estrogen antagonism may be a general axis of aging rather than a reproductive-only effect.

Exercise and stress (human data)

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Testosterone and DHT accelerate resolution of influenza-induced pulmonary inflammation in male mice; testosterone depletion or castration worsens morbidity and prolongs inflammatory monocyte and eosinophil accumulation in the lungs.[48] Intense interval exercise raised testosterone ~38% post-exercise in trained male athletes (along with prolactin and estradiol).[49]

One hour of chopping trees with axes raised salivary testosterone by 48.6% in 51 Tsimane forager-farmers aged 16–80, with no effect of age on the rise (within-subject field study in lowland Bolivia); a soccer match in the same population raised it by 30.1%.[50]

In 15 previously sedentary men who built running to about 56 km/week over 6 months, total testosterone and free androgen index fell significantly; PRL and cortisol also fell, while single-sample LH/FSH and LH pulse frequency (n=5) did not change, and weight loss did not correlate with the testosterone drop.[51]

Zinc status

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Zinc deficiency is directly linked to low testosterone. A controlled study in healthy men found that dietary zinc restriction produced a significant decline in serum testosterone, while zinc supplementation in marginally deficient elderly men raised testosterone levels.[52] Serum testosterone was significantly correlated with cellular zinc concentrations across all age groups. Since zinc is required for steroidogenesis and is antagonized by copper and iron excess, adequate zinc intake from foods like oysters, liver, and eggs is relevant to maintaining healthy androgen levels. See Zinc.

Social behavior

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A pre-registered placebo-controlled trial found no support for testosterone increasing utilitarian moral reasoning; if anything, testosterone-treated participants showed greater sensitivity to moral prohibitions than placebo.[53] Contrary to the stereotype that testosterone promotes aggression or antisocial behavior, a double-blind placebo-controlled study (91 healthy men) found that transdermal administration of 50 mg of testosterone significantly reduced lying compared to placebo.[54] Participants in a die-roll task where they could increase their payoff by misreporting results did so less under testosterone. This finding contributes to the evidence that testosterone promotes prosocial behavior (status-seeking through honesty rather than deception) and counters the framing of testosterone as purely an "aggression" hormone.

Two large-scale randomized controlled trials found no evidence that exogenous testosterone impairs men's cognitive empathy (accuracy at inferring others' mental states), contradicting the popular assumption that testosterone blunts social/emotional sensitivity.[55]

Belief about testosterone can override its real effect. In a double-blind ultimatum-bargaining game (n=60), women given a single sublingual dose of testosterone offered significantly more money than those given placebo; but subjects who merely believed they had received testosterone, regardless of what they actually got, offered 0.92 money units less than those who believed they got placebo, a belief effect larger than the real testosterone effect. Actual testosterone made offers fairer; the cultural stereotype that testosterone causes selfish, aggressive behavior made people act that way when they thought they had taken it.[56]

A placebo-controlled trial found a single 0.5mg testosterone dose increased women's implicit sense of agency and produced more optimistic affective forecasting versus placebo.[57] A single-dose finding does not establish that men's natural age-related decline drives reduced agency or cognitive decline.

I haven't heard of any bad effects from DHT, but that might be because it's so rarely used... A little DHT should be safe, but I don't think mesterolone is safe in any quantity.

— Ray Peat[58]

Peat put normal daily androgen production for young men at about 4 mg testosterone and 15 mg DHEA, with roughly half that amount effective for middle-aged men absent other problems, suggesting typical TRT dosing often overshoots physiological replacement.[59]

Sperm counts and environmental exposure

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Active-duty U.S. military women reported infertility rates near 37% versus ~12% nationally, with male service members showing comparably poor reproductive markers despite high fitness standards.[60] A 2017 meta-analysis of 185 studies (~45,000 men) found sperm concentration declined 52.4% and total sperm count declined 59.3% among unselected men in North America, Europe, Australia, and New Zealand between 1973 and 2011, with no sign of the decline leveling off.[61] Environmental estrogens such as BPA are among the suspected contributors. Estrogen is a population-level, multi-generational hazard as well as an individual one; see Estrogen: Environmental estrogens.

  • Sperm metabolism and motility: Swim-up–selected bull sperm with higher motility show higher metabolic rates and longer flagella than low-motility sperm, supporting energetic intensity as a direct determinant of fertilization capacity.[62] Progesterone and pregnenolone sulfate activate the sperm CatSper calcium channel; physiological testosterone and hydrocortisone (cortisol) inhibit progesterone-driven CatSper activation, while estradiol did not alter basal currents. The plant triterpenoids pristimerin and lupeol reduced hyperactivation.[63]

Medical uses/Effects

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In triple-negative breast cancer, androgen-receptor expression correlated with better prognosis and DHT inhibited glucocorticoid-promoted cell migration and SGK1 induction.[64] In older men, dihydrotestosterone, not free testosterone, was most consistently inversely associated with insulin resistance and incident diabetes over roughly ten years of follow-up.[65] Higher serum DHT associated with lower long-term prostate-cancer mortality in a prospective cohort, contradicting androgen-deprivation assumptions.[66] Sebum palmitate-to-stearate ratio rises with androgenic steroids and falls with prolactin, offering a non-invasive skin-lipid index of whole-body androgenic versus estrogenic tone.[67]

Androgen receptor requirement

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Androgen-receptor knockout chickens produce testosterone yet lack combs, wattles, sexual behavior, and fertility; exogenous testosterone cannot induce male secondary traits without functional AR, underscoring receptor signaling over circulating hormone alone.[68] Topical testosterone in oil is closer to physiological pulsatile delivery than large injection doses. Progesterone and adequate Thyroid are prerequisites for healthy androgen status.[69]

Low-T symptoms (fatigue, low libido, poor recovery) overlap Hypothyroidism; addressing thyroid, estrogen/progesterone, PUFA, and endotoxin takes priority over androgen supplementation.

Testosterone replacement

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TRT supplies exogenous testosterone for clinical hypogonadism or age-related decline, under medical care. Its costs come with careless dosing: suppression of the body's own production and aromatization to estrogen. Sleep, food, thyroid status and estrogen load are the first things to sort out when the symptoms are ambiguous. See Dihydrotestosterone and Pregnenolone.

Oral free testosterone vs. esters

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In rhesus monkeys, a testosterone-releasing disk worn on the navel for 46 days held a fairly steady plasma level, and bioavailability was more than twice that of testosterone placed directly on the navel.[70] Free (unesterified) testosterone is orally bioavailable on its own, unlike esters such as undecanoate which require dissolving in oil and taking with a fatty meal to absorb at all.[71] In eunuchs and castrates with no endogenous testosterone, oral free testosterone (100mg 4 times daily, or 400mg/day) produced normal male serum testosterone levels and was clinically effective in a double-blind trial, with artificial testosterone derivatives showing no advantage in either effect or cost.[72] A follow-up study of men on continuous oral free testosterone reported liver function remaining normal over long-term use, in contrast to 17α-methyltestosterone and other alkylated androgens, which are established as hepatotoxic.[73] A separate trial found that 400mg/day of oral free testosterone for 21 days accelerated hepatic drug-metabolizing enzyme activity (antipyrine half-life fell from 8.0 to 5.7 hours) without any adverse change in liver markers (albumin, bilirubin, prothrombin, transaminases).[74]

Liver disease (NAFLD, NASH, cirrhosis)

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Italian clinical series from the 1960s–1970s reported high rates of improvement or remission in hepatic cirrhosis with combined high-dose injectable testosterone and thiamine (vitamin B1).[75] In a high-fat-diet NASH rabbit model, oral LPCN 1144 (lipid-based testosterone undecanoate formulation) improved NASH histology, reduced hepatic fibrosis markers, and corrected HFD-induced low testosterone and insulin resistance; co-formulation with alpha-tocopherol showed additive benefit.[76] In men with type 2 diabetes, higher serum total testosterone is independently associated with lower odds of NAFLD; no similar association was seen for androgens in women in the same cohort, see Testosterone in women below.[77]

Testosterone in women

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Testosterone has an anabolic role in women alongside estrogen and progesterone, made by the ovaries and adrenals through the same Pregnenolone → DHEA pathway used in men.

Elevated testosterone in women (as in PCOS) is usually read as purely pathological, but part of the rise may be adaptive rather than incidental: prolonged stress promotes sodium loss, and androgens act directly on the kidney to increase sodium reabsorption. Female rats given testosterone developed higher blood pressure and lower urinary sodium excretion than untreated females on the same high-sodium diet.[78] See Polycystic ovary syndrome for the fuller thyroid/estrogen/stress mechanism this fits into.

In women over 70 with no prior cardiovascular disease, low blood testosterone and DHEA, not low estrogen, predicted double the risk of a cardiovascular event compared to women with higher testosterone.[79]

In 284 women on long-term subcutaneous testosterone therapy, self-reported hair thinning reversed and none reported new hair loss despite serum testosterone roughly fourfold above normal; lower pretreatment testosterone correlated with prior hair loss.[80]

Adiposity vs age

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In NHANES 2011–2016 men aged 20–59 (n = 4,984), chronological age explained only 2.5% of circulating total testosterone variation, while DXA percent body fat, visceral adipose tissue area, and waist circumference each explained about 18–20%; waist circumference performed at least as well as DXA visceral fat. Biochemically low testosterone (<300 ng/dL) tracked substantially higher adiposity in every age decade.[81]

Mutual antagonism with glucocorticoids in fat storage

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The androgen receptor is expressed and functional during early human fat-cell differentiation, and its activation inhibits fat maturation. Glucocorticoids tightly regulate and inhibit androgen-receptor expression, facilitating fat storage, particularly in visceral fat, confirming a bidirectional antagonism between androgens and glucocorticoids in body-fat regulation.[82]

Diet and testosterone

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In a meta-analysis of intervention studies, low-fat diets lowered total, free, and urinary testosterone and DHT in men compared with high-fat diets, with no change in LH or SHBG.[83]

A systematic review and meta-analysis of 27 studies (309 men, 12 randomized) found the effect of low-carbohydrate diets on testosterone depends on protein intake, not carbohydrate restriction itself: high-protein (over 3.4 g/kg bodyweight/day) low-carbohydrate diets lowered total testosterone by roughly 5.23 nmol/L, while low-carbohydrate diets with lower protein intake showed no consistent decrease. The same review found low-carbohydrate diets raised resting and post-exercise cortisol short-term (under 3 weeks), with resting cortisol normalizing afterward while the post-exercise rise persisted.[84]

In seven men fed equal calories and fat for ten days per diet, a high-carbohydrate diet gave higher testosterone and lower cortisol than a high-protein diet.[85]

Androgens overview

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Androgens are steroid hormones that support anabolic metabolism, mood, and tissue repair in both sexes. Testosterone and dihydrotestosterone (DHT) are the main examples in humans.

Low androgen symptoms are downstream of Thyroid suppression, Estrogen excess, PUFA load, and chronic Stress, not isolated gonadal failure alone.[86][87]

History (Androgen)

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Etymology (Androgen)

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The name combines Greek andro- ("male") with "-gen" ("producing"), describing the class of hormones that produce male characteristics.

The term was coined in the 1930s as researchers characterized testosterone, androsterone, and related compounds as a distinct hormone family.

Androgen means "male-maker" (Greek). Testosterone was isolated in the 1930s. Clinical use of androgen replacement expanded in the 20th century alongside synthetic anabolic steroids.

Structure/Chemical properties

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Androgens are C19 steroids derived from Pregnenolone via DHEA. Testosterone aromatizes to estradiol; 5α-reductase converts testosterone to DHT.

Function/Mechanism of Action

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Mainstream endocrinology: androgens bind androgen receptors to support protein synthesis, libido, and erythropoiesis.

When the diet has chronically contained more polyunsaturated fats than can be oxidized immediately or detoxified by the liver, the fat stores will contain a disproportionate amount of them... These PUFA stimulate the stress hormones, ACTH, cortisol, adrenaline, glucagon, and prolactin, which increase lipolysis, producing more fatty acids in a vicious circle.

— Ray Peat[88]

Intense interval exercise raised testosterone ~38% post-exercise in trained male athletes (human study), alongside prolactin and estradiol.[89]

Sodium butyrate, a gut-bacterial HDAC inhibitor, potentiates androgen receptor transcriptional activity independent of raising androgen levels; HDAC inhibition increased both basal and androgen-induced AR transcription, including androgen-dependent PSA expression, without increasing nuclear AR protein.[90]

Medical uses/Effects (Androgen)

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Pharmaceutical androgens treat hypogonadism and some anemias. Physiological delivery (topical testosterone in oil) is favored over megadose TRT when supplementation is used at all.[87] Progesterone and adequate Thyroid are upstream supports to correct before turning to androgen shots.

Side/Adverse effects

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Excess androgen therapy can aromatize to estrogen, suppress gonadotropins, and raise hematocrit. Addressing thyroid, estrogen/progesterone balance, PUFA, and gut Endotoxin takes priority over targeting androgens alone.

Androstenedione

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Androstenedione molecular structure
Androstenedione molecular structure

Androstenedione is a weak androgen made in the adrenals and gonads, an intermediate on the pathway from DHEA to testosterone and estrone. It converts to testosterone via 17-beta-hydroxysteroid dehydrogenase and to estrone via aromatase; after menopause, when ovarian follicles are depleted, androstenedione becomes the main hormone secreted by the residual ovary, and peripheral aromatization of it is a major source of postmenopausal estrogen. It was sold over the counter in the US as a bodybuilding/anti-aging supplement (marketed to raise testosterone) until the FDA declared it an adulterated dietary ingredient in March 2004, and Congress reclassified it as a controlled anabolic steroid later that year.[91]

Peat's view

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The placenta converts 16-hydroxy androstenedione and 16-hydroxy-DHEA into estriol; their decline reflects fetal exhaustion or a dying fetal-placental system.[92]

Function/Mechanism of Action (androstenedione)

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Because androstenedione is a direct aromatase substrate, its physiological effects in older or menopausal females run partly through the estrogen it is converted into rather than through direct androgen action. In middle-aged, ovariectomized (surgically menopausal) rats, higher circulating androstenedione correlated with more working- and reference-memory errors on maze tasks, and the highest dose tested impaired performance directly. Unopposed estrogen harms brain function.[93] A related line of research found that blocking aromatase (preventing conversion of androgens like androstenedione into estrogen) reversed memory impairment in ovariectomized rats, and that the mainstream claim of estrogen as protective against Alzheimer's-type memory decline lacks supporting evidence.[94]

A randomized controlled trial in 30 healthy young men (aged 19-29) tested this aromatization pathway directly: 300 mg/day of oral androstenedione for 8 weeks did not raise serum testosterone at all, but serum estradiol rose from a baseline of 220 pmol/L to 310 pmol/L at 2 weeks, and serum estrone rose from 106 pmol/L to 153 pmol/L over the same period, while HDL cholesterol fell from 42 mg/dL to 37 mg/dL. The supplement produced no extra strength or muscle-fiber gains over placebo, the estrogen conversion was the only measurable hormonal effect.[95]

In 24 fertile versus 18 infertile men, geometric-mean intratesticular androstenedione was about 64% lower in the infertile group (79.6 versus 222 nmol/kg) with no matching difference in peripheral plasma; tissue testosterone was similar in both groups.[14]

HPTA

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HPTA (hypothalamic-pituitary-thyroid-adrenal axis) names the brain-pituitary-thyroid-adrenal loop that sets metabolic rate and stress-hormone output. Endocrinology often splits this into separate HPA and HPT axes; The page treats them as one stress-energy system.

When the diet has chronically contained more polyunsaturated fats than can be oxidized immediately or detoxified by the liver, the fat stores will contain a disproportionate amount of them... These PUFA stimulate the stress hormones, ACTH, cortisol, adrenaline, glucagon, and prolactin, which increase lipolysis, producing more fatty acids in a vicious circle. In the relative absence of PUFA, the stress reaction is self limiting.

— Ray Peat[96]

The maladaptive sequence, starting from stress or hypothyroidism, would typically involve increased absorption of endotoxin, leading to interference with mitochondrial respiration, a shift to fat oxidation, inflammation, and the increase of a wide range of stress hormones.

— Ray Peat[97]

Chronic Stress keeps thyroid output low and shifts cells toward glycolytic Lactic acid production in Peat's writing.[98] Intense exercise raised cortisol, prolactin, and estradiol acutely in athletes: interval running to exhaustion produced immediate post-exercise increases of 45% in estradiol, 38% in testosterone, and 230% in prolactin.[99] Aspirin blunted several exercise-related pituitary hormone spikes in a human RCT.[100] Recovery themes: adequate Thyroid, Progesterone, Glucose, salt, lower PUFA, Aspirin, niacinamide, reduced gut Endotoxin. See Cortisol, Hypothyroidism, Roadmap/06 - Activities, Harm reduction.

SHBG

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SHBG (sex hormone-binding globulin) is a liver-produced protein that binds testosterone and estrogen in blood, lowering the free (biologically active) fraction of each. Only unbound hormone can bind tissue receptors and exert effects; total hormone measurements can look normal while SHBG-driven changes in the free fraction change how much reaches tissue.

What raises and lowers it

[edit]

No specific Ray Peat commentary naming SHBG was found in archive searches for this page. In mainstream endocrinology, the liver increases SHBG output when it senses high estrogen or thyroid hormone, and decreases it when androgens rise, insulin spikes, or metabolic stress increases, so thyroid status and liver health both shape SHBG independent of the sex hormones it binds. SHBG changes over months in response to metabolic health, thyroid signaling, hormone therapy, weight change, and reproductive-life-stage transitions, not day to day.

Clinical associations

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Low SHBG is a consistent feature of insulin resistance and metabolic syndrome: in cross-sectional data on men, lower SHBG associates with the cluster of abdominal obesity, dyslipidemia, and insulin resistance that defines metabolic syndrome.[101] In a registry of hypogonadal men, over a third met criteria for metabolic syndrome, and this group had significantly lower SHBG and total testosterone than those without it. Men in the lowest testosterone quartile (<7.1 nmol/L) had more than double the odds of metabolic syndrome versus the highest quartile.[102] High SHBG, conversely, can leave free testosterone and free estrogen low even when total hormone levels look adequate on a standard panel.

Practice

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Interpret free and total sex hormones together with SHBG, not SHBG alone; a single SHBG value without paired free-hormone measurement is hard to act on. See Testosterone, Estrogen, Insulin resistance, Thyroid, Liver, Metabolic syndrome.

See also

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References

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  1. ↑ 1.0 1.1 Ray Peat, "Unsaturated Vegetable Oils: Toxic," raypeat.com.
  2. ↑ Ray Peat, "Prostate cancer," raypeat.com.
  3. ↑ Ray Peat, "Leaky Vessels, Leaky Cells, Leaky Minds," raypeat.com.
  4. ↑ Josephs RA, Cobb AR, Lancaster CL, et al. "Dual-hormone stress reactivity predicts downstream war-zone stress-evoked PTSD," Psychoneuroendocrinology. 2017;78:76-84. doi:10.1016/j.psyneuen.2017.01.013. PMID 28178580.
  5. ↑ Nätt D, et al. "High-sugar diet and human sperm," PLoS Biol. 2019. doi:10.1371/journal.pbio.3000559.
  6. ↑ Chung SSW, et al. "Oral administration of a retinoic acid receptor antagonist reversibly inhibits spermatogenesis," Endocrinology. 2011. doi:10.1210/en.2010-0941.
  7. ↑ Moustafa A, et al. "Hindlimb unloading-induced reproductive suppression via Downregulation of hypothalamic Kiss-1 expression in adult male rats," Reprod Biol Endocrinol. 2021. PMID 33663539.
  8. ↑ Maeda N, Fujiki J, Hasegawa Y, et al. "Testicular induced corticosterone synthesis in male rats under fasting stress," Steroids. 2022;177:108947. doi:10.1016/j.steroids.2021.108947. PMID 34843801.
  9. ↑ 9.0 9.1 9.2 Tremellen K, McPhee N, Pearce K, Benson S, Schedlowski M, Engler H. "Endotoxin-initiated inflammation reduces testosterone production in men of reproductive age," Am J Physiol Endocrinol Metab. 2018;314(3):E206-E213. doi:10.1152/ajpendo.00279.2017. PMID 29183872. PMCID PMC5899218. Randomized placebo-controlled endotoxin challenge (0.8 ng/kg IV, 17 vs 16 healthy lean men aged 18-40) plus an observational study of 75 fertility-clinic men.
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  85. ↑ Diet-hormone interactions: protein/carbohydrate ratio alters reciprocally the plasma levels of testosterone and cortisol and their respective binding globulins in man n=7 men, 10 days per diet, equal calories and fat; testosterone 468 ± 34 vs 371 ± 23 ng/dL (p < 0.05), cortisol 7.74 ± 0.71 vs 10.6 ± 0.4 µg/dL (p < 0.05), high carbohydrate vs high protein; SHBG and CBG moved in parallel. doi:10.1016/0024-3205(87)90086-5. PMID 3573976.
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  100. ↑ Acetylsalicylic acid inhibits the pituitary response to exercise-related stress in humans
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  102. ↑ Bhattacharya RK, Khera M, Blick G, et al. "Effect of 12 months of testosterone replacement therapy on metabolic syndrome components in hypogonadal men: data from the Testim Registry in the US (TRiUS)," BMC Endocr Disord. 2011;11:18. 849 men, 37% with metabolic syndrome; SHBG; total testosterone; lowest vs highest quartile (≥11.5 nmol/L) odds ratio 2.66.