1. Thesis
Hormones are a control system, not a scoreboard.
The endocrine system exists to hold things in range. It is a network of feedback loops, and almost every number it produces is meaningful only in context — the time of day it was drawn, the binding proteins carrying it, the pituitary signal driving it, and whether the person has symptoms at all.
Two opposite errors dominate this field, and BioSignal rejects both.
The first error is under-treatment. Genuine endocrine disease is common, diagnosable, and highly treatable. Hypothyroidism, hypogonadism, and menopause have effective evidence-based therapies. Women have been systematically under-treated for menopausal symptoms for two decades because of a widely misinterpreted trial — a failure that caused real suffering.
The second error is "optimisation". A large commercial industry now sells hormone testing and hormone therapy to people who are not deficient, on the premise that more is better. It is not. Pushing hormones above physiological range carries real risks — infertility, erythrocytosis, atrial fibrillation — for benefits that have not been demonstrated in people with normal levels.
The discipline that separates good endocrinology from both errors is the same: diagnose properly, treat what is actually deficient, and address the cause rather than the number.
2. How The System Actually Works
Most hormone axes run on negative feedback through the hypothalamus and pituitary:
- Thyroid axis: hypothalamus → TSH from the pituitary → thyroid hormone (T4, T3) → feeds back to
suppress TSH. Because the relationship between TSH and T4 is log-linear, TSH is exquisitely sensitive — a small fall in thyroid hormone produces a large rise in TSH. This is why TSH, a pituitary hormone, is the best first-line test of the thyroid.
- Gonadal axis: hypothalamus → LH/FSH from the pituitary → testosterone or oestradiol. Whether LH is
high or low tells you whether the problem is in the gonad (primary) or above it (secondary) — which is why measuring the hormone alone is never enough.
- Adrenal axis: hypothalamus → ACTH → cortisol, with a strong diurnal rhythm: high on waking,
low at night.
The clinical consequence of feedback: a hormone level cannot be interpreted without the signal that drives it. This single fact invalidates most direct-to-consumer hormone testing, which measures outputs without the controllers.
3. Binding Proteins: Why "Total" Is Often The Wrong Number
Most circulating sex hormone is bound to sex hormone-binding globulin (SHBG) and albumin, and only the free fraction is biologically active.
SHBG is not a constant. It falls with obesity, insulin resistance, and hypothyroidism, and rises with ageing, oestrogen, and hyperthyroidism. A man with obesity can therefore have a low total testosterone with normal free testosterone — because his SHBG is low, not because he is androgen-deficient.
This is one of the most common sources of misdiagnosis in men's health, and it is routinely exploited: measure total testosterone in a middle-aged man with a high BMI, find it "low", and sell him therapy for a problem he may not have.
4. Thyroid: Where Diagnosis Is Good and Over-Treatment Is The Risk
Hypothyroidism is common, usually autoimmune (Hashimoto's), and straightforward to diagnose: a raised TSH with a low free T4. Levothyroxine replacement is effective, cheap, and one of the genuine success stories of endocrinology.
The difficulties are at the edges.
Subclinical hypothyroidism — a raised TSH with a normal free T4 — is where most over-treatment happens. The TRUST trial, in older adults, found that levothyroxine produced no improvement in symptoms or tiredness compared with placebo. Treating a number that is not causing disease exposes people to the risks of over-replacement (atrial fibrillation, bone loss) for no demonstrated benefit.
T4/T3 combination therapy and desiccated thyroid extract are widely promoted for people who feel unwell on levothyroxine despite a normal TSH. Randomised trials have generally not shown combination therapy to be superior, though some patients report preferring it. Desiccated thyroid extract delivers a non-physiological T3:T4 ratio with variable potency and is not recommended in guidelines. The honest position: the persistent-symptoms problem is real and poorly solved, and the popular alternatives have not been shown to solve it.
5. Testosterone: Treat Deficiency, Not Ageing
Male hypogonadism requires both symptoms and repeatedly low morning fasting testosterone — a single low result is not a diagnosis. LH and FSH then distinguish primary (testicular) from secondary (pituitary/hypothalamic) failure.
The most important clinical point is that much "low testosterone" is functional and reversible. Obesity, obstructive sleep apnoea, opioids, excess alcohol, and acute illness all suppress testosterone. Treating the cause frequently restores it. Prescribing testosterone instead treats the number while the cause continues.
What the evidence shows. The Testosterone Trials found modest benefits in men with genuinely low levels: improved sexual function, some improvement in mood and bone density and anaemia — and no cognitive benefit. The TRAVERSE trial, in men with hypogonadism and cardiovascular risk, found testosterone was non-inferior for major adverse cardiac events — an important reassurance — but observed increases in atrial fibrillation, pulmonary embolism, and acute kidney injury.
What testosterone therapy costs. It suppresses the body's own production and impairs spermatogenesis — a fact that is under-disclosed and matters enormously to men who want children. It also raises haematocrit, requiring monitoring.
What it is not. It is not an anti-ageing therapy, and there is no established benefit for men with normal levels.
6. Menopause: The Trial That Was Misread
This is the clearest case in medicine of a misinterpretation causing decades of harm.
What happened. The Women's Health Initiative reported in 2002, and its findings were communicated in a way that led to the near-collapse of menopausal hormone therapy use worldwide. Women were left untreated for genuinely debilitating symptoms.
What the evidence actually supports now. The key variable is timing. For women under 60, or within 10 years of menopause, and without contraindications, the benefits of hormone therapy for vasomotor symptoms generally outweigh the risks, and the absolute risks are small. Notably, in the WHI's oestrogen-only arm (women who had had a hysterectomy), breast cancer incidence was not increased. The increased breast-cancer signal was associated with combined oestrogen–progestogen therapy and with duration of use — a real risk, but a modest absolute one that must be weighed against real benefit.
Menopausal hormone therapy is the most effective treatment for vasomotor symptoms. It also prevents bone loss. It is not recommended as a therapy for chronic disease prevention.
Route matters: transdermal oestrogen carries a lower venous thromboembolism risk than oral.
Vaginal oestrogen for genitourinary symptoms deserves separate mention: systemic absorption is minimal, it is highly effective, and fear generalised from systemic therapy leads many women to suffer unnecessarily.
Non-hormonal options exist and are genuinely useful for women who cannot or prefer not to take hormones: NK3-receptor antagonists (fezolinetant), SSRIs/SNRIs, gabapentin, and cognitive behavioural therapy.
7. PCOS: A Metabolic Condition With a Reproductive Name
Polycystic ovary syndrome is diagnosed by the Rotterdam criteria — two of three: irregular or absent ovulation, clinical or biochemical hyperandrogenism, and polycystic ovarian morphology on ultrasound.
The name is unhelpful. The cysts are not the disease, and many women with PCOS do not have them. Insulin resistance is central, which is why PCOS is as much a cardiometabolic condition as a reproductive one, and why it links directly to type 2 diabetes and MASLD.
Effective management: weight management where relevant, metformin for the metabolic component, combined oral contraceptives for cycle regulation and hyperandrogenism, and letrozole — not metformin — as first-line for ovulation induction when fertility is the goal.
8. Cortisol and "Adrenal Fatigue"
Cortisol follows a strong diurnal rhythm and rises with acute stress and illness. Genuine disorders of the adrenal axis exist and are serious: Cushing's syndrome (excess) and Addison's disease (insufficiency). Both are diagnosable with proper testing.
"Adrenal fatigue" is not a recognised medical diagnosis. The concept — that chronic stress "exhausts" the adrenal glands into underproducing cortisol — has been examined and is not supported by evidence. Systematic reviews have found no consistent relationship between the salivary cortisol profiles sold as evidence for it and the symptoms attributed to it.
This matters for two reasons. The symptoms people bring — fatigue, poor sleep, low mood — are real, and they deserve a proper diagnostic workup rather than a label that forecloses it. And a genuine adrenal insufficiency mistaken for "adrenal fatigue" is dangerous.
9. Supplements: Evaluated Proportionally
Deliberately placed after physiology, diagnosis, and clinical treatment — because that is their proportion of the evidence.
Ashwagandha has the most credible evidence of the popular hormonal supplements: small randomised trials report reduced stress scores and cortisol. But the trials are small and short, extracts differ, and much of the literature comes from a narrow set of research groups with commercial ties. The testosterone evidence is weaker still. Importantly, there is a genuine hepatotoxicity signal: cases of liver injury have been reported internationally, and some regulators have issued warnings. Ashwagandha may also raise thyroid hormone levels, which matters for anyone with thyroid disease.
DHEA, tongkat ali, tribulus, "testosterone boosters", and "hormone balancing" blends: not established. Where effects on testosterone are reported at all, they are typically small, in men who were stressed or deficient, and of no demonstrated clinical consequence.
Vitamin D and zinc correct deficiency, and correcting deficiency is worthwhile. Supplementing them in replete people does not raise testosterone.
The general principle: no supplement has been shown to meaningfully raise testosterone in a healthy man, to treat hypothyroidism, or to replace hormone therapy in menopause. Where a hormone is genuinely deficient, the treatment is the hormone — under clinical supervision.
10. What Actually Moves Hormones (Without a Prescription)
The unglamorous levers are the real ones:
- Sleep. Testosterone is largely produced during sleep; restriction measurably lowers it. Treating
obstructive sleep apnoea can restore it.
- Body composition. Adipose tissue converts testosterone to oestradiol and lowers SHBG. Weight loss
raises testosterone. Obesity is probably the single largest driver of low testosterone in men today.
- Resistance training. Preserves muscle and bone, improves insulin sensitivity, and supports
hormonal health across the lifespan — with much better evidence than any hormonal supplement.
- Alcohol and opioids. Both suppress the gonadal axis. Opioid-induced hypogonadism is common and
frequently missed.
11. What The Evidence Does Not Support
- Testosterone therapy for men with normal levels ("optimisation")
- Treating a single low testosterone result without confirmation and symptoms
- Levothyroxine for most subclinical hypothyroidism, particularly in older adults
- Desiccated thyroid extract
- "Adrenal fatigue" as a diagnosis, and the salivary cortisol panels sold to detect it
- Direct-to-consumer hormone panels interpreted without the pituitary signals that control them
- Supplements marketed to raise testosterone in healthy men
- Avoiding vaginal oestrogen for genitourinary symptoms out of fear generalised from systemic therapy
12. Practical Summary
If you have symptoms: get properly assessed. Endocrine disease is common and treatable, and under-treatment is as real a problem as over-treatment.
If a hormone is low: ask why before asking for a prescription. Obesity, sleep apnoea, opioids, alcohol, and illness are common, reversible causes.
If you are in menopause with vasomotor symptoms: hormone therapy is the most effective treatment, and for most women under 60 within 10 years of menopause the benefits outweigh the risks. The 2002 headlines were misread. Discuss it properly.
If your TSH is mildly raised but your T4 is normal: you may well not need treatment, especially if you are older.
If you want to help your hormones without a prescription: sleep, lose excess fat, lift weights, and drink less. That is the honest list.
13. Open Questions
- Why do a subset of people on levothyroxine remain symptomatic with a normal TSH, and what actually
helps them?
- Is there a genuine benefit of T3 in any identifiable subgroup?
- What are the long-term effects of testosterone therapy on cardiovascular and prostate outcomes?
- Can the timing hypothesis in menopausal hormone therapy be refined into individual risk prediction?
- Does the hepatotoxicity signal with ashwagandha reflect the herb, the extract, or contamination?
14. Sources (verify-to-source pass required before publication)
- Endocrine Society Clinical Practice Guideline: Testosterone Therapy in Men with Hypogonadism
- The Testosterone Trials (T-Trials)
- TRAVERSE cardiovascular safety trial of testosterone
- Women's Health Initiative (WHI) and subsequent timing-hypothesis reanalyses
- The Menopause Society (formerly NAMS) position statement on hormone therapy
- NICE guideline: Menopause — diagnosis and management
- ATA Guidelines for the Treatment of Hypothyroidism
- TRUST trial (levothyroxine in subclinical hypothyroidism in older adults)
- International evidence-based guideline for the assessment and management of PCOS
- Systematic reviews examining the "adrenal fatigue" hypothesis
- Regulatory safety communications on ashwagandha and hepatotoxicity