Our Hormonal System

A hormone is a chemical messenger your body produces in one place, releases into the bloodstream, and uses to control something happening somewhere else entirely. A hormone made in your brain can change what's happening in your testes, your bones, your fat tissue, and your mood, all at the same time. That's what makes the endocrine system so powerful, and why disruptions to it have such wide-ranging effects. Hormones split into two main types based on what they're built from:

Steroid hormones (testosterone, oestrogen, cortisol, progesterone, DHT) are built from cholesterol. They're fat-soluble, which means they pass straight through cell membranes and bind to receptors inside the cell, usually in the nucleus, where they directly influence which genes get read. This is why steroid hormones have such deep, structural effects, testosterone telling a muscle cell to make more protein, cortisol telling your liver to release glucose, oestrogen telling a fibroblast to produce more collagen, all the result of a steroid hormone reaching the nucleus and flipping switches on the DNA.

Peptide hormones (LH, FSH, GnRH, insulin, growth hormone) are protein-based and water-soluble. They can't pass through the cell membrane, so they bind to receptors on the cell's surface and trigger signalling cascades inside. This is how LH hits a Leydig cell and triggers the entire testosterone production chain without ever entering the cell.

The endocrine system is a network of glands communicating through these messengers, most of them regulated by feedback loops. Hormone rises, the gland slows down. Hormone falls, the gland ramps back up.

The endocrine system

Each gland has a specific role, but they don't operate independently, they influence each other constantly through feedback loops and shared signalling pathways.

Hypothalamus sits at the base of the brain and is the master regulator. It links the nervous system to the endocrine system, translating signals from the brain (stress, sleep, temperature, energy status) into hormonal commands. It produces releasing hormones like Gonadotropin-Releasing Hormone GnRH (which controls sex hormones), CRH (which controls cortisol), and TRH (which controls thyroid hormones). Almost every hormonal cascade in the body starts here.

Pituitary gland. Sits just below the hypothalamus and relays its commands to the rest of the body. The anterior pituitary produces LH, FSH, ACTH, TSH, growth hormone, and prolactin. The posterior pituitary releases oxytocin and vasopressin. When the hypothalamus sends a releasing hormone, the pituitary responds by secreting the matching stimulating hormone into the bloodstream, which travels to the target gland.

Thyroid. Sits in the front of the neck and controls metabolic rate, energy, and body temperature through T3 and T4. Every cell in the body has thyroid receptors, which is why thyroid dysfunction affects everything, weight, energy, mood, hair, skin, heart rate, cognition. Controlled by TSH from the pituitary, which is controlled by TRH from the hypothalamus.

Pancreas. Sits behind the stomach and produces insulin and glucagon, the two hormones that regulate blood sugar. Insulin lowers it by telling cells to absorb glucose. Glucagon raises it by telling the liver to release stored glucose. Insulin resistance, where cells stop responding properly to insulin, is the underlying dysfunction in type 2 diabetes and is tightly linked to testosterone, body composition, and chronic inflammation.

Adrenals. Sit on top of each kidney. The outer cortex produces steroid hormones: cortisol, DHEA and DHEA-S (both controlled by ACTH from the pituitary), and aldosterone (controlled separately by the kidneys via the RAAS system). The inner medulla produces adrenaline and noradrenaline, the fight-or-flight hormones, and is wired directly to the sympathetic nervous system, which is why the response is almost instant.

Testes (in men) are both reproductive organs and endocrine glands. They contain Leydig cells, which produce testosterone in response to LH from the pituitary, and Sertoli cells, which support sperm production in response to FSH. The testes are the endpoint of the HPG axis and the primary source of testosterone in men.

Ovaries (in women) produce oestrogen, progesterone, and testosterone. They contain follicles that mature under FSH stimulation and release eggs during ovulation triggered by an LH surge. The ovaries are the endpoint of the HPG axis in women and cycle through different hormonal phases monthly, making female endocrinology more time-dependent than male.

Pineal gland sits deep in the centre of the brain and produces melatonin.

These glands don't operate in silos. The hypothalamus and pituitary sit on top of multiple parallel axes (HPG for sex hormones, HPA for stress, HPT for thyroid) that cross-talk constantly. Cortisol suppresses GnRH. Thyroid hormones influence SHBG. Insulin resistance affects testosterone. Inflammation suppresses the HPG axis at multiple levels.

The HPG axis

The HPG axis (hypothalamic-pituitary-gonadal axis) is the master control system for sex hormone production in both sexes. It's a three-tier feedback loop between the hypothalamus, the pituitary gland, and the gonads (testes in men, ovaries in women).

The hypothalamus releases a peptide hormone called GnRH (gonadotropin-releasing hormone) in rhythmic pulses. Faster, higher-frequency pulses favour LH release. Slower, lower-frequency pulses favour FSH release. GnRH itself has a very short half-life, it's released, does its job, and is cleared within minutes.

GnRH pulses travel a very short distance from the hypothalamus to the anterior pituitary through a dedicated blood vessel network. When GnRH hits gonadotroph cells in the pituitary, they respond by releasing luteinising hormone (LH) and follicle-stimulating hormone (FSH).

In men, LH travels to the testes and binds to Leydig cells, triggering testosterone production. FSH binds to Sertoli cells, which support sperm production (spermatogenesis).

In women, FSH stimulates follicle development in the ovaries during the first half of the menstrual cycle. As the dominant follicle matures, it produces increasing oestrogen. When oestrogen reaches a critical threshold, it triggers a massive LH surge from the pituitary, which causes ovulation. After ovulation, the remnant follicle becomes the corpus luteum and produces progesterone. Both LH and FSH also drive ovarian production of testosterone.

The testes and ovaries receive the LH and FSH signals, produce the sex hormones (testosterone, oestrogen, progesterone), and those hormones then feed back to the hypothalamus and pituitary to regulate the system and reduce their output of GnRH and LH.

When testosterone rises high enough in a man's blood, the hypothalamus detects it and reduces GnRH pulse frequency and amplitude. Less GnRH means less LH, which means less testosterone. When testosterone drops, the brake comes off and the cycle ramps back up. This is why exogenous testosterone shuts down natural production, the brain sees plenty in the blood and stops signalling, the testes go quiet, and over time the testes atrophy and sperm production drops. Oestradiol feeds back on the HPG axis the same way.

In women, oestradiol has both negative and positive feedback depending on timing. For most of the cycle, rising oestrogen suppresses GnRH (negative feedback). But at a critical threshold mid-cycle, it flips and triggers a massive LH surge (positive feedback), which is the trigger for ovulation. This positive feedback mechanism is unique to women.

More things that suppress the HPG axis:

Chronic stress and elevated cortisol. The HPA axis (hypothalamus → pituitary → adrenals (cortisol)) runs parallel to the HPG axis and directly interferes with it. Cortisol suppresses GnRH at the hypothalamus, makes pituitary cells less responsive to whatever GnRH does arrive, and directly impairs Leydig cell testosterone production at the gonads.

Severe caloric restriction. Leptin, the hormone fat cells produce to tell the hypothalamus how much energy is stored, drops with fat loss. The hypothalamus reads low leptin as "energy is scarce, not a safe time to reproduce."

Poor sleep. GnRH pulses are strongest during sleep, and most of your daily testosterone secretion happens overnight.

Excess body fat. Fat cells produce leptin in proportion to mass, and in obesity the hypothalamus becomes leptin resistant. And fat tissue contains aromatase, the enzyme that converts testosterone to oestradiol. More body fat means more testosterone gets converted to oestrogen, meaning more suppressive signal.

Chronic inflammation. Pro-inflammatory cytokines like TNF-α and IL-6 suppress the HPG axis at every level.

Testosterone

Testosterone is the primary androgen hormone in the human body. In men it drives muscle growth, fat distribution, bone density, libido, energy, mood, cognitive sharpness, and the development of every male sexual characteristic from puberty onward. It is the single most important hormone for male physical and mental performance. In women, testosterone is produced in smaller amounts but is still essential for libido, bone strength, muscle tone, mood, and cognitive function.

A lot of what you experience day to day, energy levels, body composition, mental clarity, drive, recovery from training, even how you handle stress, traces back to whether their testosterone is doing its job properly.

How testosterone is synthesised:

When LH reaches a Leydig cell, it kicks off a chain of signals that ends with the cell pulling cholesterol out of storage. Cholesterol is the raw material for every steroid hormone in the body, including testosterone.

A transport protein called StAR shuttles cholesterol into the cell's mitochondria, where the first enzyme in the chain (P450scc) clips it into pregnenolone. Pregnenolone then moves out of the mitochondria to another part of the cell, where a sequence of enzymes converts it step by step into testosterone. The final enzyme in the chain is 17β-HSD, the one that makes the last conversion to testosterone itself.

In men, Leydig cells produce roughly 95% of circulating testosterone. They are the only place in the male body that runs the full pathway from cholesterol all the way to finished testosterone.

The remaining ~5% comes from the adrenal glands, but indirectly. The adrenal cortex doesn't make testosterone directly. It makes precursors, primarily DHEA and DHEA-S (the sulphated, storage form of DHEA). DHEA is the dominant adrenal androgen by volume, men produce roughly 10-30 mg of it per day, compared to about 6-7 mg of testosterone per day from the testes. But almost none of that DHEA stays as DHEA.

It circulates in the blood and gets converted to testosterone (and oestrogen) in peripheral tissues like fat, skin, and to a smaller extent muscle, by enzymes those tissues express locally.

Total testosterone, free testosterone, and SHBG

When testosterone enters the bloodstream, it doesn't float around freely. About 60-65% binds tightly to a protein called sex hormone-binding globulin (SHBG). Another 30-35% binds loosely to albumin. Only about 2-4% remains completely unbound, this is free testosterone.

SHBG-bound testosterone is essentially locked up. It can't enter cells, it can't bind to androgen receptors, it can't do anything and it serves as a reservoir and a buffer. By binding testosterone, SHBG extends its half-life in the bloodstream, keeping a stable circulating pool rather than sharp spikes and crashes. It also prevents all your testosterone from hitting receptors at once.

Albumin binds testosterone the same way it binds most fat-soluble molecules in the blood, by physical association rather than a tight chemical lock. The grip is weak. As blood moves slowly through capillary beds in muscle, bone, and brain, testosterone easily slips off albumin and enters cells just like free testosterone would. This is why both fractions are grouped together as bioavailable testosterone (free + albumin-bound), which makes up roughly two-thirds of your total.

But total testosterone alone can be misleading. A man with a total testosterone of 500 ng/dL and high SHBG might have less bioavailable testosterone than a man at 400 ng/dL with low SHBG. This is why free testosterone as a separate, critical marker. If your total testosterone looks "normal" but you have symptoms of low T (fatigue, low libido, brain fog, poor recovery, loss of muscle), you need to check free testosterone and SHBG.

Oestrogen is one of the strongest drivers of SHBG, it stimulates the liver to produce more SHBG, which is why women on oral contraceptives have very high SHBG. Thyroid hormones (T3/T4) also increase SHBG production. Aging raises SHBG. Liver disease, low caloric intake, and low body fat also raise it.

Insulin directly suppresses SHBG production in the liver, which is why obesity, insulin resistance, and type 2 diabetes are all associated with low SHBG. Underactive thyroid lowers it. Exogenous androgens suppress it. Low SHBG means more free testosterone technically, but it also means faster clearance, and it usually comes packaged with metabolic dysfunction.

Testosterone acts by entering cells and binding to androgen receptors (ARs), which then move into the nucleus and directly influence gene expression. Androgen receptors are found in virtually every tissue in the body.

Testosterone’s effects on Muscle

Testosterone is the primary hormonal driver of muscle growth. Free testosterone passes directly through the muscle cell membrane, binds to an androgen receptors, and the receptor-testosterone complex moves into the nucleus where it binds to specific DNA sequences called androgen response elements which directly upregulates the genes involved in muscle protein synthesis, telling the nucleus to read the protein-building instructions more often.

Testosterone also activates satellite cells, muscle-specific stem cells that sit dormant on the outside of muscle fibres. When activated, they proliferate and fuse with existing muscle fibres, donating their nuclei. his is one of the reasons muscle built on higher testosterone can be retained more easily even after levels drop, the extra nuclei persist for a long time (this is the cellular basis of "muscle memory").

Testosterone also slows muscle breakdown. It inhibits the ubiquitin-proteasome pathway, the body's main system for tearing down and recycling proteins. So it's not just building more, it's preventing the loss of what's already there.

On top of that, testosterone increases local production of IGF-1 (insulin-like growth factor 1) inside muscle tissue. IGF-1 hits the mTOR pathway, one of the cell's primary "build" switches, which independently ramps up protein synthesis. IGF-1 also pulls more glucose into the muscle cell for fuel, recruits more satellite cells, and keeps existing muscle cells alive longer under training stress.

Testosterone’s effects on Bones

Testosterone maintains bone mineral density both directly through androgen receptors on osteoblasts (bone-building cells) and indirectly through conversion to oestradiol via aromatase, which is the primary hormonal protector of bone in both sexes. Men with low testosterone are at increased risk of osteoporosis and fractures.

Testosterone's effects on Brain and Mood

The brain is a highly testosterone-sensitive organs. Androgen receptors are found throughout most key brain structures, and testosterone influences multiple neurotransmitters, specific brain regions, and the brain's physical infrastructure simultaneously.

Serotonin. Testosterone modulates serotonin transporter expression and serotonin receptor density in the brain. When testosterone is low, serotonin signalling becomes less efficient, which is one of the direct mechanisms linking low testosterone to depression, irritability, and anxiety.

Dopamine. Testosterone increases dopamine synthesis and release in the mesolimbic pathway, the brain's reward and motivation circuit. Low testosterone reduces dopamine output in this circuit, which is why low T often presents as apathy, lack of motivation, and reduced ambition.

Amygdala and emotional processing. Testosterone and its neurosteroid metabolites enhance GABAergic signalling within the amygdala. Which means the fear and threat-detection neurons are harder to fire. Second, serotonin projects heavily into the amygdala, and when testosterone supports serotonin signalling, adequate testosterone helps keep the amygdala's response to negative stimuli measured. Third, testosterone and cortisol have opposing effects on the amygdala, cortisol increases its sensitivity to threats (useful during acute danger), while testosterone dampens it. Which is why men with low testosterone and stress often experience anxiety that feels disproportionate.

Hippocampus and memory. Testosterone supports neurogenesis (the birth of new neurons) & synaptic plasticity (protects existing neurons) in the hippocampus.

Prefrontal cortex and executive function. The prefrontal cortex handles decision-making, impulse control, planning, and focus. Testosterone influences dopaminergic signalling in this region, supporting cognitive clarity and the ability to sustain attention. Brain fog, difficulty concentrating, and reduced mental sharpness in men with low testosterone trace partly to reduced prefrontal cortex activation.

Cerebral blood flow. Testosterone promotes vasodilation in cerebral arteries, increasing blood flow to the brain. More blood flow means more oxygen and glucose delivery to neurons.

Neuroprotection. Oestradiol is actually the primary neuroprotective hormone in both sexes, which is why crashing oestrogen can cause cognitive fog and mood disturbance even when testosterone levels are high.

Testosterone’s effect on Libido and Sexual function

Testosterone is the primary hormonal driver of sexual desire in both men and women, but the relationship is more nuanced than "more testosterone = more libido."

It influences libido through the same dopaminergic pathways described above, testosterone drives dopamine release in the mesolimbic reward circuit, and sexual desire is partly a dopamine-mediated motivational state. Testosterone also directly influences nitric oxide production in erectile tissue, which is the mechanism behind erections (nitric oxide relaxes smooth muscle in the blood vessels of the penis, allowing blood flow in).

There appears to be a threshold effect: below a certain level (roughly 300-400 ng/dL, though it varies individually), libido drops noticeably. Above that threshold, more testosterone doesn't proportionally increase desire. A man at 500 ng/dL and a man at 900 ng/dL may have similar libido if both are above their personal threshold.

Testosterone’s effect on Fat distribution

Testosterone promotes fat loss through several specific pathways. It increases lipolysis (the breakdown of stored fat) by upregulating beta-adrenergic receptors on fat cells, making them more responsive to adrenaline and noradrenaline, the signals that tell fat cells to release their stored energy. It also inhibits lipoprotein lipase (LPL), an enzyme on the surface of fat cells that pulls circulating fat (triglycerides) out of the bloodstream and into fat storage. Less LPL activity means less fat being captured and stored. More muscle mass also means a higher basal metabolic rate, so you burn more calories at rest.

Men with adequate testosterone tend to be leaner overall, and preferentially carry less visceral fat (the metabolically dangerous fat packed around organs in the abdominal cavity). When testosterone drops, fat distribution shifts toward visceral accumulation specifically, which is where the metabolic problems come from. Visceral fat secrete pro-inflammatory cytokines (TNF-α, IL-6) and also contain high concentrations of aromatase.

Testosterone’s effect on the Cardiovascular system

Erythropoiesis (red blood cell production). Testosterone stimulates the kidneys to produce erythropoietin (EPO), the hormone that tells bone marrow to produce more red blood cells. It also acts directly on bone marrow stem cells to promote red blood cell development. Adequate red blood cell production means efficient oxygen delivery to tissues, which supports energy, endurance, and recovery.

Vasodilation and nitric oxide. Testosterone promotes the production of nitric oxide (NO) in blood vessel walls. Nitric oxide relaxes the smooth muscle in arterial walls, causing vasodilation, which lowers blood pressure and improves blood flow to tissues including the heart, brain, and muscles.

Cardiac muscle. The heart itself has androgen receptors. Testosterone influences cardiac muscle contractility, energy metabolism within heart cells, and cardiac output.

The U-shaped risk curve. Both very low and supraphysiologically high testosterone levels are associated with increased cardiovascular risk. Low testosterone is linked to increased visceral fat, insulin resistance, chronic inflammation, reduced nitric oxide production, and higher fibrinogen, all of which are independent cardiovascular risk factors. The cardiovascular sweet spot appears to be physiological testosterone levels with well-managed oestradiol, because oestrogen is cardioprotective, supporting HDL, nitric oxide production, and anti-inflammatory effects in blood vessel walls.

Testosterone’s effect Immune function

Testosterone is broadly immunosuppressive, meaning it dials down the immune system's activity across multiple levels.

T-cell suppression. T-cells (the adaptive immune system's coordinators) have androgen receptors. Testosterone enters T-cells and downregulates the genes involved in their activation and cytokine production, meaning fewer immune cells get mobilised and the ones that do are less aggressive in their response.

Cytokine profile shift. Testosterone shifts the balance of cytokine production away from pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and toward anti-inflammatory cytokines (IL-10). Less inflammation means less tissue damage from immune overreaction, but also a less aggressive response to genuine threats.

Reduced antibody production. Testosterone suppresses B-cell activity. B-cells are the immune cells that produce antibodies to tag pathogens for destruction.

Macrophage modulation. Testosterone reduces macrophage activation and their production of inflammatory mediators. Macrophages are the frontline immune cells that engulf pathogens and present them to T-cells to initiate the adaptive response.

Thymic involution. Testosterone accelerates the shrinkage of the thymus, the gland where T-cells mature. This permanently reduces the body's capacity to produce new, naive T-cells.

Testosterone drives muscle growth, bone density, aggression, and reproductive behaviour, all of which are metabolically expensive. The immune system is also enormously energy-demanding. So testosterone essentially diverts resources toward physical performance and reproductive fitness at the expense of immune vigilance. Meaning men are more susceptible to bacterial, viral, and parasitic infections. Men have higher mortality from infections like influenza and COVID-19. Men produce weaker antibody responses to vaccines. Women's higher oestrogen levels upregulate immune activity, which gives them stronger pathogen responses but also makes them more vulnerable to the immune system turning on itself.

Age-related decline

Testosterone production peaks in the late teens to early twenties. From about age 30 onward, total testosterone declines at roughly 1-2% per year in the average man, with free testosterone declining slightly faster because SHBG tends to increase with age.

By the time a man is 70-80, mean testosterone levels in healthy men sit around 380-400 ng/dL, compared to roughly 530 ng/dL in men aged 19-39. But the variation between individuals is enormous, some 80-year-olds have higher testosterone than some 30-year-olds. Lifestyle, body composition, and metabolic health play a massive role in the trajectory.

At the testicular level, Leydig cells become less responsive to LH with age with each cell producing less. At the hypothalamic level, GnRH pulse frequency and amplitude decrease.

Testosterone in women

Women produce testosterone from the ovaries, the adrenal glands, and peripheral conversion of precursor hormones (DHEA, androstenedione) in tissues like fat, muscle, and skin. Total production is roughly 0.1-0.4 mg per day compared to 3-10 mg per day in men. Normal total testosterone in premenopausal women is roughly 15-70 ng/dL.

Testosterone levels in women decline gradually with age starting in the late twenties to early thirties. By menopause, testosterone levels are roughly half of what they were at peak. Women who have their ovaries removed (oophorectomy) experience an abrupt and severe drop in testosterone, often with immediate symptoms.

The most well-documented effect of testosterone in women is on libido. Loss of sexual desire is extremely common in menopausal and post-menopausal women, and a significant proportion of cases respond to testosterone supplementation when oestrogen replacement alone doesn't resolve it.

Testosterone also supports bone density, with higher free testosterone levels associated with lower hip fracture risk. It maintains muscle mass and strength, which becomes increasingly important after menopause when the accelerated loss of both bone and muscle can compound into frailty. It also contributes to cognitive function, energy levels, and overall sense of wellbeing.

Oestrogen (Estradiol)

In men, oestradiol is produced in men almost entirely by the enzyme aromatase converting testosterone into oestradiol in tissues like fat, brain, bone, and the testes. Men don't have a dedicated oestrogen-producing gland, their oestrogen supply depends on having adequate testosterone and functioning aromatase.

In women, the ovaries are the primary source before menopause, with the adrenals and peripheral aromatase contributing. After menopause, peripheral aromatase becomes the dominant source.

For men, the practical sweet spot is roughly 20-35 pg/mL, though it varies individually. For women, oestradiol doesn't sit at a steady level, it fluctuates dramatically across the menstrual cycle: early follicular phase (during and just after the period) it's at its lowest, roughly 30-50 pg/mL. It rises through the follicular phase and peaks just before ovulation at roughly 200-400 pg/mL, sometimes higher. After ovulation it drops, rises again modestly in the mid-luteal phase (roughly 100-300 pg/mL), then falls again to trigger menstruation. After menopause, oestradiol drops to roughly 5-25 pg/mL and stays there.

Oestradiol drives the menstrual cycle, with levels fluctuating significantly across the follicular phase, ovulation (where oestradiol peaks and triggers the LH surge), and the luteal phase. These fluctuations are why women's mood, energy, libido, and cognitive function can vary meaningfully across the cycle.

At menopause, ovarian oestrogen production drops by roughly 80-90%. Leading to accelerated bone loss, increased cardiovascular risk, skin collagen loss, cognitive changes, mood disruption, vaginal atrophy, joint stiffness, and the vasomotor symptoms (hot flashes, night sweats) that characterise the transition.

What oestradiol does

Bone density. Oestradiol is the primary hormonal protector of bone in both sexes, more so than testosterone. It suppresses osteoclast activity (the cells that break down bone), meaning it slows bone resorption.

Cardiovascular protection. Oestradiol promotes nitric oxide production in blood vessel walls (vasodilation, lower blood pressure, better blood flow), supports HDL levels, and suppresses inflammatory signalling in vascular tissue. The endothelium (inner lining of arteries) has oestrogen receptors, and oestradiol acting on those receptors suppresses adhesion molecule expression (making it harder for immune cells to stick to the vessel wall and initiate the inflammatory cascade that leads to atherosclerosis), promotes endothelial repair, and maintains the integrity of the vascular lining.

Brain and neuroprotection. Oestradiol is the primary neuroprotective hormone in both sexes. In the brain, aromatase converts testosterone to oestradiol locally within neurons. This locally produced oestradiol suppresses neuroinflammation, reduces oxidative stress, supports synaptic plasticity in the hippocampus (memory), and protects against excitotoxicity.

Joint health. Oestradiol maintains synovial fluid production and cartilage integrity in joints. One of the most immediate and recognisable symptoms of crashed oestrogen in men is joint pain, stiffness, and cracking.

Libido. Oestradiol has a U-shaped relationship with libido in men. Too low kills desire through the loss of dopaminergic support and general central nervous system depression. Too high also kills desire through enhanced serotonin inhibition of the dopamine reward circuit, potential prolactin elevation, and increased SHBG binding up free testosterone.

Collagen and skin. Oestradiol directly stimulates fibroblast activity and collagen production. The rapid skin aging women experience post-menopause, thinning, loss of elasticity, increased wrinkling, is directly driven by the loss of oestrogen's stimulatory effect on dermal collagen.

Lipid metabolism. Oestradiol supports HDL production and helps regulate LDL clearance from the bloodstream. This is part of its cardioprotective effect and is why lipid profiles tend to worsen when oestrogen is suppressed.

Aromatase (CYP19A1)

Aromatase (CYP19A1) is the enzyme that converts testosterone to oestradiol and androstenedione to oestrone. It's found in adipose tissue (fat), brain, bone, skin, blood vessels, and the testes. The amount of aromatase activity you have determines how much of your testosterone gets converted to oestrogen.

Aromatase activity increases with body fat, aging, chronic inflammation, insulin resistance, and alcohol consumption. Overweight men tend to have disproportionately high oestrogen.

Oestrogen in men

The body's aromatase system generally maintains an appropriate testosterone-to-oestradiol ratio naturally but becomes relevant with exogenous testosterone (where the external testosterone provides more substrate for aromatase) and obesity (where excess adipose tissue creates excessive aromatase activity).

Symptoms of high oestradiol in men are water retention and bloating, sensitive or puffy nipples (early gynecomastia), mood swings and emotional volatility, reduced libido, increased anxiety, and fat gain particularly around the chest and hips.

Symptoms of low oestradiol in men are joint pain and stiffness, dry skin, flat mood and emotional numbness, low libido, fatigue, and poor cognitive function.

DHT (Dihydrotestosterone)

DHT is the other downstream product of testosterone. Where aromatase converts testosterone to oestradiol, the enzyme 5-alpha reductase converts testosterone to DHT. About 5-7% of circulating testosterone gets converted to DHT daily, producing roughly 200-300 mcg per day. DHT is 3-5 times more potent than testosterone at the androgen receptor. It's mostly a local hormone, produced and used on-site in the skin, hair follicles, prostate, and genitals.

The normal range for DHT in adult men is roughly 30-80 ng/dL, though some men need higher levels for optimal libido and drive.

5-alpha reductase: the conversion enzyme

There are two main isoforms of the enzyme. Type 1 (SRD5A1) is found primarily in non-genital skin, hair follicles, the liver, and certain brain areas. Type 2 (SRD5A2) is found primarily in the prostate, genital skin, seminal vesicles, and facial/chest hair follicles. Type 2 is responsible for roughly two-thirds of circulating DHT and is the isoform most relevant to both the benefits and the problems associated with DHT.

Finasteride inhibits only type 2.

Dutasteride inhibits both type 1 and type 2. Dutasteride produces a more complete DHT suppression (roughly 90%+ reduction) compared to finasteride (roughly 60-70% reduction).

What DHT does

Fetal development. DHT is essential for the formation of male external genitalia in the womb. Testosterone is converted to DHT by 5-alpha reductase in genital tissue, and DHT drives the development of the penis, scrotum, and prostate.

Puberty. DHT drives the further growth of the penis and scrotum, facial and body hair development, voice deepening, and prostate growth during puberty.

Libido and sexual function in adults. DHT's role in adult male libido is debated. Some studies suggest testosterone alone may be sufficient for sexual function. However, finasteride clinical trials consistently show sexual side effects (reduced libido, weaker erections, diminished ejaculatory volume) in a subset of users. The practical reality is that some men experience meaningful sexual side effects from DHT reduction and others notice nothing.

Drive, confidence, and aggression. DHT contributes to the subjective sense of assertiveness, confidence, and competitive drive that men associate with feeling "on." This is related to its greater potency at the androgen receptor, particularly in the brain.

The problems with DHT

Hair loss. DHT is the primary hormonal driver of male pattern hair loss in genetically susceptible individuals. Paradoxically, DHT promotes facial and body hair growth while destroying scalp hair. In susceptible follicles, DHT binds to androgen receptors and activates genes that progressively shorten the growth phase of the hair cycle and shrink the follicle. Not all men lose their hair despite having similar DHT levels.

Prostate enlargement (BPH). The prostate contains high concentrations of 5-alpha reductase type 2 and produces large amounts of DHT locally. This local DHT stimulates prostate cell growth, which is normal during development but becomes problematic with age. More than 50% of men over 50 have some degree of benign prostatic hyperplasia (BPH), where the prostate grows large enough to compress the urethra and cause urinary symptoms. This is why 5-alpha reductase inhibitors were originally developed.

Acne and oily skin. DHT stimulates sebaceous glands (oil glands) in the skin to produce more sebum. Excess sebum can clog pores and contribute to acne.

Prolactin

Prolactin is a peptide hormone produced by lactotroph cells in the anterior pituitary. Its primary biological function is stimulating milk production (lactation) in women after childbirth. Elevated prolactin in men or non-lactating women is one of the most common and underdiagnosed causes of low libido, sexual dysfunction, and emotional flatness.

The dopamine-prolactin axis

The lactotroph cells in the pituitary will continuously produce and release prolactin unless they are actively inhibited. The primary inhibitor is dopamine. Dopamine from the hypothalamus travels down to the pituitary through the tuberoinfundibular pathway and binds to D2 receptors on lactotroph cells, suppressing prolactin release. When dopamine tone is adequate, prolactin stays low. When dopamine drops, prolactin rises.

High prolactin is almost always a sign of low dopamine tone, and low dopamine is what produces the motivational and sexual symptoms people experience.

What elevated prolactin does

Kills libido. Elevated prolactin is associated with suppressed sexual desire through multiple pathways. The low dopamine tone that allowed prolactin to rise is itself the primary driver, the mesolimbic reward circuit that generates desire is underperforming. On top of this, prolactin suppresses GnRH at the hypothalamus (reducing LH and therefore testosterone production), and it appears to directly inhibit sexual arousal circuits in the brain.

Causes erectile dysfunction. Hyperprolactinaemia is associated with erectile dysfunction independent of testosterone levels. The mechanism is primarily through the same low dopamine state, which is involved in the central arousal pathways.

Emotional flatness. Elevated prolactin reflects low dopamine tone, so men with high prolactin often describe feeling emotionally flat, unmotivated, and apathetic.

Suppresses the HPG axis. Prolactin suppresses GnRH secretion from the hypothalamus, which reduces LH and FSH, which reduces testosterone production.

What raises prolactin

Post-orgasm. Prolactin surges after orgasm in both men and women. This is the hormonal basis of the refractory period, the temporary loss of sexual desire and arousal after ejaculation. The prolactin spike suppresses dopamine briefly.

Medications. Antipsychotics (which block D2 dopamine receptors) are the most common pharmacological cause of elevated prolactin. Certain antidepressants (SSRIs, through serotonin's effect on dopamine), metoclopramide, and opioids can also raise prolactin.

Stress. Physical and psychological stress can elevate prolactin, partly through serotonin's modulatory effect on prolactin release and partly through direct stress-pathway activation.

Pituitary adenomas (prolactinomas). Benign tumours of the lactotroph cells are the most common pituitary tumour and can produce very high prolactin levels and are treated with dopamine agonists (
Cabergoline, bromocriptine), which shrink the tumour by restoring dopamine suppression of the lactotroph cells.

Oestrogen. Oestrogen directly stimulates the lactotroph cells in the pituitary through oestrogen receptors (ERα) on those cells. It drives both cell proliferation (more prolactin-producing cells) and increased prolactin gene transcription per cell (each cell produces more). It also reduces D2 receptor expression on lactotroph cells, making them less responsive to dopamine's inhibitory signal. This can amplify sexual dysfunction beyond oestrogen's own effects.

Normal ranges and testing

Normal prolactin in men is roughly 2-18 ng/mL. In women, roughly 2-29 ng/mL (higher range reflects oestrogen's stimulatory effect). Levels above 25-30 ng/mL in men warrant investigation. Levels above 100 ng/mL strongly suggest a prolactinoma.

Cortisol

Cortisol is the body's primary stress hormone, produced in the zona fasciculata of the adrenal cortex in response to ACTH from the pituitary. It's a steroid hormone built from cholesterol, just like testosterone, oestrogen, and DHT, and it acts through the same mechanism: crossing cell membranes, binding to intracellular receptors (glucocorticoid receptors, which are found in virtually every cell), moving into the nucleus, and altering gene expression.

Acutely (minutes to hours), cortisol is useful. It raises blood sugar by telling the liver to release stored glucose (gluconeogenesis), increases the availability of tissue-repair substrates, suppresses inflammation, and enhances memory formation.

Chronically (weeks to months of sustained elevation), cortisol becomes destructive across virtually every system:

Muscle breakdown. Cortisol is catabolic and promotes protein breakdown in muscle tissue (proteolysis) to generate amino acids that the liver can convert to glucose. Chronically elevated cortisol actively degrades muscle.

Fat accumulation. Chronic cortisol promotes visceral fat deposition specifically, it increases appetite, drives insulin resistance, and redirects fat storage toward the abdominal region.

HPG axis suppression. Cortisol suppresses GnRH at the hypothalamus, reduces pituitary sensitivity to GnRH, and directly impairs Leydig cell function.

Immune suppression. Chronically suppresses the immune system broadly, reducing T-cell activity, antibody production, and inflammatory cytokine release.

Hippocampal damage. The hippocampus (memory centre) has a high density of glucocorticoid receptors and is one of the most cortisol-sensitive structures in the brain. Chronic cortisol exposure damages hippocampal neurons, impairs neurogenesis, and reduces synaptic plasticity. Leading to cognitive decline, memory problems, and the brain fog.

Bone loss. Cortisol inhibits osteoblast activity (bone building) and promotes osteoclast activity (bone breakdown).

Collagen degradation. Cortisol directly inhibits collagen synthesis and thins the skin.

Insulin resistance. Chronic cortisol promotes insulin resistance by increasing hepatic glucose output (the liver keeps dumping glucose into the bloodstream even when blood sugar is already adequate) leading to metabolic dysfunction

Impaired recovery from training. Cortisol elevated during the recovery window, particularly overnight, actively works against the anabolic processes that repair and build muscle. Elevated nighttime cortisol disrupts sleep architecture, reducing deep sleep and therefore reducing GH output.

Gut and digestion. Cortisol suppresses digestive function, blood flow is diverted away from the gut, enzyme secretion is reduced, and gut motility slows.

Cardiovascular effects. Chronic cortisol raises blood pressure through sodium retention and increased vascular sensitivity to catecholamines (adrenaline, noradrenaline).

In chronic stress, the HPA feedback loop can become dysregulated. The hypothalamus and pituitary can become partially resistant to cortisol's feedback signal, meaning the axis stays activated even though cortisol is already elevated. The system gets stuck in "on" mode. This is the endocrine basis of chronic stress, burnout, and the patterns that eventually lead to the cortisol-DHEA-S imbalance.

Cortisol rhythm

Cortisol follows a predictable daily (circadian) rhythm. It peaks in the early morning (the cortisol awakening response, which helps you wake up and feel alert), then declines throughout the day, reaching its lowest point around midnight. Disrupted cortisol patterns, elevated at night (preventing sleep) or flattened throughout the day (no morning peak, low energy all day), are markers of HPA axis dysregulation and are associated with poor sleep, fatigue, metabolic dysfunction, and impaired recovery from training.

DHEA-S

DHEA-S (dehydroepiandrosterone sulfate) is a steroid hormone produced primarily in the zona reticularis of the adrenal cortex, the same layer that produces DHEA. DHEA-S is the sulfated (and more stable, longer-lasting) form of DHEA, and it's the most abundant circulating steroid hormone in the body. It serves as a precursor hormone, a raw material that peripheral tissues convert into testosterone and oestrogen as needed.

DHEA-S role

Precursor to sex hormones. DHEA-S is converted to DHEA in peripheral tissues, and DHEA is then converted to androstenedione, which can become either testosterone or oestrogen depending on which enzymes act on it.

Cortisol counterbalance. DHEA-S and cortisol are both produced by the adrenal cortex, both driven by ACTH from the pituitary. In acute stress, both rise together. But in chronic, sustained stress, their trajectories diverge and cortisol tends to stay elevated while DHEA-S production declines over time. This creates an imbalanced ratio, high cortisol relative to low DHEA-S, which is what's often described as "adrenal fatigue."

Independent effects. Beyond its role as a precursor, DHEA-S has anti-inflammatory, neuroprotective, and immune-modulating properties. Low DHEA-S is associated with increased cardiovascular risk, reduced immune function, cognitive decline, and increased mortality in elderly populations.

DHEA-S follows the steepest age-related decline of any hormone. It peaks in the mid-twenties and drops by roughly 2-3% per year thereafter. By age 70-80, DHEA-S levels can be 10-20% of what they were at peak. Which means the cortisol-to-DHEA-S ratio naturally shifts unfavourably with age even without chronic stress.

Normal DHEA-S ranges for adult men are roughly 280-640 mcg/dL (though this varies by age and lab). For women, roughly 65-380 mcg/dL.

Progesterone

Progesterone is typically thought of as a female reproductive hormone, but it also plays roles in both sexes.

Progesterone in women

Progesterone is produced primarily by the corpus luteum in the ovary after ovulation. During the luteal phase (the second half of the menstrual cycle), progesterone rises significantly and prepares the uterine lining for potential implantation of a fertilised egg. If pregnancy occurs, progesterone remains elevated (eventually produced by the placenta) to maintain the pregnancy. If pregnancy doesn't occur, the corpus luteum degrades, progesterone drops, and the uterine lining sheds (menstruation).

Beyond reproduction, progesterone has significant effects on the brain and nervous system. It's a precursor to allopregnanolone, a potent neurosteroid that enhances GABAergic signalling. Meaning progesterone has calming, anxiolytic, and sleep-promoting effects. The drop in progesterone before menstruation is one of the hormonal drivers of premenstrual anxiety, irritability, and sleep disruption, the GABA-enhancing signal is withdrawn.

After menopause, progesterone drops to near zero because there is no ovulation and therefore no corpus luteum.

Progesterone in men

Men produce small amounts of progesterone in the testes and adrenal glands. It's an intermediate in the steroidogenic pathway (cholesterol → pregnenolone → progesterone → further downstream hormones), so it exists as a transit molecule in testosterone synthesis.

Like in women, it converts to allopregnanolone in the brain, contributing to GABAergic modulation, sleep quality, and anxiety regulation. Some men on 5-alpha reductase inhibitors (finasteride) report anxiety, insomnia, and mood disturbance partly because finasteride also blocks the conversion of progesterone to its neurosteroid metabolites, reducing GABA-enhancing activity in the brain.

Progesterone also has anti-oestrogenic effects in certain tissues, competing with oestradiol for receptor binding. .

Normal progesterone in men is low, roughly 0.3-1.2 ng/mL. It's not routinely tested.

Thyroid hormones (T3 and T4)

The thyroid gland controls how fast every cell in your body runs. It sets the metabolic rate, the baseline speed of energy production, protein synthesis, oxygen consumption, and heat generation in virtually every tissue. Every cell in the body has thyroid receptors, which is why thyroid dysfunction affects everything simultaneously: weight, energy, mood, hair, skin, heart rate, cognition, digestion, cholesterol levels, and recovery from training.

The thyroid gland sits in the front of the neck and produces two hormones: T4 (thyroxine) and T3 (triiodothyronine). T4 is the primary output, produced in much larger quantities, but it's relatively inactive. T3 is the active form, roughly 3-5 times more potent, and it's what actually binds to thyroid receptors inside cells and drives metabolic activity.

The HPT axis

The thyroid is controlled by the same three-tier feedback loop structure as the HPG and HPA axes.

1 - Hypothalamus. The hypothalamus releases TRH (thyrotropin-releasing hormone).

2 - Anterior pituitary. TRH stimulates thyrotroph cells in the anterior pituitary to release TSH (thyroid-stimulating hormone) into the bloodstream.

3 - Thyroid gland. TSH travels to the thyroid and stimulates the follicular cells to produce T4 and a small amount of T3. These hormones are synthesised using iodine (essential dietary mineral) and tyrosine (amino acid).

Negative feedback. When T3 and T4 levels in the blood rise high enough, they feed back to the hypothalamus and pituitary through thyroid hormone receptors, suppressing TRH and TSH output. When thyroid hormones drop, TSH rises to drive the thyroid harder.

TSH is the most sensitive screening marker for thyroid dysfunction and moves first, before T3 or T4 go out of range.

What thyroid hormones do

Metabolic rate. T3 enters cells, binds to nuclear thyroid receptors, and directly upregulates the genes involved in energy production, oxygen consumption, and heat generation. (higher basal metabolic rate)

Body temperature. Thyroid hormones are the primary regulator of core body temperature through their effect on metabolic heat production.

Heart rate and cardiovascular function. T3 directly increases heart rate and cardiac contractility.

Cholesterol metabolism. Thyroid hormones upregulate LDL receptor expression on liver cells, increasing the rate at which LDL is cleared from the bloodstream.

Protein synthesis. T3 stimulates protein synthesis throughout the body, supporting muscle maintenance, tissue repair, and growth.

Brain function. Thyroid hormones are essential for cognitive function, concentration, and mental processing speed. In fetal development, thyroid hormones are critical for brain development.

Gut motility. T3 stimulates smooth muscle contraction in the digestive tract.

Hair, skin, and nails. Thyroid hormones support the growth cycle of hair follicles and the turnover of skin cells.

Thyroid dysfunction

Hypothyroidism is an underactive thyroid producing too little hormone. Symptoms build slowly and often get blamed on other things: fatigue, mild weight gain, cold intolerance, dry skin, thinning hair, brain fog, low mood, low libido, slow training recovery, elevated cholesterol.

Hyperthyroidism is the opposite, an overactive thyroid producing too much. Symptoms mirror hypothyroidism: weight loss, anxiety, tremor, heat intolerance, rapid heart rate, insomnia, irritability, diarrhoea.

Either direction disrupts the rest of the hormonal system. Hypothyroidism worsens insulin resistance, promotes weight gain, and lowers SHBG. Hyperthyroidism raises SHBG sharply, which can drop bioavailable testosterone and cause low-androgen symptoms even when total testosterone reads normal.

Subclinical thyroid dysfunction is when TSH is off (high in subclinical hypo, low in subclinical hyper) but T4 still sits within the reference range. The system is compensating but hasn't fully decompensated yet. Many people in this zone feel symptomatic and improve on treatment, even though their numbers "look fine" by standard lab criteria.

T4-to-T3 conversion

The thyroid can be producing adequate T4, TSH can look normal, but the person feels hypothyroid because the conversion of T4 to T3 in peripheral tissues is impaired.

Deiodinase enzymes handle this conversion, and they require selenium as a cofactor.

common causes:

Chronic stress and elevated cortisol down-regulate T4-to-T3 conversion and increase the production of reverse T3 (rT3), an inactive metabolite that occupies thyroid receptors without activating them (the body does this deliberately to conserve energy during stress & slow metabolism).

Caloric restriction and low-carb diets trigger the same downregulation. The body reads energy restriction as a signal to conserve, and reducing T3 production.

Selenium deficiency directly impairs deiodinase function. Without adequate selenium, the enzymes can't convert T4 to T3 efficiently.

Iron deficiency impairs thyroid peroxidase activity (the enzyme the thyroid itself uses to produce T4) and may also affect peripheral conversion.

Chronic inflammation suppresses T4-to-T3 conversion through cytokine-mediated effects on deiodinase expression.

Liver dysfunction. The liver performs a significant portion of T4-to-T3 conversion.

This is the scenario where a standard thyroid panel (TSH only, or TSH plus free T4) looks "normal" but the person feels terrible. TSH is normal because the thyroid is producing adequate T4. Free T4 is normal because the raw material is there. But free T3 is low because the conversion step is failing. Testing free T3 is the only way to catch this.

Leptin

Leptin is the hormone fat cells use to tell the brain how much energy is stored in the body. It's the master signal that ties body composition, appetite, metabolic rate, thyroid function, and reproductive function together through a single input.

Leptin is produced almost entirely by adipocytes (fat cells) in white adipose tissue, roughly in proportion to how much fat you carry.

Leptin is a "fed status" hormone

When leptin is high (adequate fat stores), the brain gets a "fed" signal: appetite drops, metabolic rate stays up, energy-conservation machinery stays off.

When leptin drops (depleting fat stores), the brain gets a "starving" signal: hunger rises, metabolic rate falls, and the body shifts aggressively into conservation mode.

Leptin is why aggressive dieting becomes harder over time: as fat drops, leptin drops, and the brain pushes back with hunger and a lower metabolic rate to defend the body's energy reserves.

Leptin controls downstream

Appetite and satiety. Adequate leptin dampens hunger through the hypothalamic circuits above. Low leptin aggressively drives hunger, food-seeking behaviour, and food reward sensitivity.

Metabolic rate. Leptin stimulates thyroid hormone production, specifically T3, and increases sympathetic nervous system activity. When leptin drops, T3 drops and total daily energy expenditure drops (metabolic adaptation).

HPG axis function. Leptin is required for normal reproductive function in both sexes. Kisspeptin neurons in the hypothalamus, the direct "on switch" for GnRH release, have leptin receptors and require adequate leptin to fire properly. When leptin drops from severe caloric restriction or low body fat, kisspeptin activity drops, GnRH drops, LH drops, testosterone drops.

Inflammation. Leptin has pro-inflammatory properties at high levels. Fat tissue producing chronically high leptin is one of the inputs into the elevated TNF-α and IL-6 pattern associated with obesity.

Leptin resistance

In obesity, leptin levels are very high (lots of fat tissue producing lots of leptin), but the brain stops responding properly to the signal. The hypothalamus becomes leptin resistant, similar to how cells become insulin resistant. The brain sees low leptin activity and hunger stays elevated and metabolic rate doesn't increase appropriately.

The causes of leptin resistance aren't fully understood but appear to involve chronic inflammation (cytokines interfering with leptin receptor signalling in the hypothalamus).

Leptin signalling is also asymmetric. The brain responds aggressively to falling leptin (driving hunger and energy conservation) and weakly to rising leptin (permitting satiety but not aggressively suppressing intake). Which makes evolutionary sense: in the environment humans evolved in, starvation was the acute threat and excess food was a rare opportunity. Modern food abundance exploits this asymmetry, which is part of why obesity develops easily and reverses with difficulty. It's also why cutting is physiologically harder than bulking. The body will aggressively resist losing fat and only weakly resist gaining it.

During a cut, periodic refeeds or diet breaks can partially restore leptin and the downstream signalling, which is why structured refeeds are a legitimate tool during prolonged cuts.

Ghrelin

Ghrelin is the functional counterpart to leptin on the short-term appetite side. Where leptin signals long-term fat status, ghrelin signals immediate hunger. It's produced primarily by cells in the stomach lining and rises when the stomach is empty, signalling the brain that it's time to eat. Ghrelin levels drop sharply after a meal and gradually rise again as the stomach empties.

Ghrelin acts on the same hunger neurons in the hypothalamus that leptin suppresses, but from the opposite direction: ghrelin stimulates them, driving hunger. It also stimulates growth hormone release from the pituitary (the name comes from "growth hormone releasing peptide"), which is one of the mechanisms by which fasting and short-term caloric restriction elevate growth hormone.

Ghrelin's relevance for most people is practical meal timing. Ghrelin is partly trained by eating patterns, it rises at times the body has learned to expect food.

During aggressive cutting, ghrelin rises alongside leptin falling. And the two signals compound.

Current pharmaceutical interest in ghrelin focuses on blocking it as a potential obesity treatment, though this has proven harder than it sounds because ghrelin has multiple redundant pathways driving hunger and simply blocking the receptor doesn't reliably suppress appetite in humans.