Hormones · Stress Physiology · Functional Investigation
A deficient hormone is not simply a gap to fill. It is information. Why the body is making less of something — whether that's a nutritional limitation, a competing demand from the stress axis, or a genuine protective response — is the clinical question that determines whether supplementing makes sense and what happens when you do.
I was on a call recently with a client who does a considerable amount of their own research — the kind of client I find most interesting to work with, because they push the conversation into territory that generic consultations never reach.
We were discussing bioidentical hormones. Specifically the role of progesterone — not just in the monthly cycle, but in the stress response, in neuroprotection, in the relationship with cortisol, and in the broader question of why the body might be producing less of it. The client brought up Ray Peat. I had a fairly strong view on where Peat gets things right and where his prescriptions become harder to follow. That conversation is what this post is about.
But before we get to Peat, we need to establish the foundational clinical question that I think gets missed in almost every conversation about hormone replacement — bioidentical or otherwise.
When a DUTCH Plus comes back showing low progesterone — which it often does in women in their late thirties and forties — there are two very different clinical responses available.
The first is to note the deficiency and supplement. Bioidentical progesterone cream, oral micronised progesterone, whatever the preferred delivery. This approach is straightforward, often produces rapid symptomatic relief, and is increasingly mainstream in integrative and functional medicine. It is also, in my view, sometimes the wrong place to start.
The second response is to ask: why is progesterone low?
These two responses lead to very different clinical outcomes. Because a hormone being deficient is not a simple statement about supply. It may be a statement about demand, about competing requirements, about the body making a prioritisation decision that makes sense in context — even if the downstream effects are unpleasant.
A deficient hormone is not simply a gap to fill. It is a question the body is asking. The clinical response should be to answer the question, not simply to fill the gap.
To understand why progesterone might be low, you need to understand where it sits in the steroidogenesis cascade — the pathway by which cholesterol is converted into all the body's steroid hormones.
The pathway begins with cholesterol, which is converted to pregnenolone — the master precursor from which all steroid hormones are ultimately derived. Pregnenolone then branches in two directions: one branch leads toward DHEA and the downstream sex hormones (testosterone, oestradiol, progesterone in its role in the luteal phase); the other leads directly toward cortisol via progesterone itself as an intermediate.
This is the critical structural point. Progesterone is not only a sex hormone. It is an obligate intermediate in the cortisol synthesis pathway. The adrenal glands use progesterone to make cortisol. And when the demand for cortisol is chronically elevated — which is to say, when someone is under sustained physiological or psychological stress — the adrenal glands will divert pregnenolone toward cortisol production.
The term sometimes used for this is pregnenolone steal — the idea that the stress axis "steals" precursor substrate from the sex hormone pathway. The mechanism is more nuanced than simple substrate competition: it involves upregulation of the enzymes that drive cortisol synthesis (particularly CYP11B1) and downregulation of those driving sex hormone synthesis. But the clinical result is what matters: sustained stress reduces progesterone availability — not because the ovaries or adrenals have failed, but because the body is correctly prioritising survival over reproduction.
If a woman in her early forties has low progesterone on her DUTCH, and she also has elevated metabolised cortisol, a flat or dysregulated diurnal cortisol curve, and low DHEA relative to cortisol — this is not primarily a progesterone problem. It is an HPA axis problem that is manifesting, in part, as low progesterone.
Giving her progesterone supplementation in this context may provide short-term symptomatic relief. She may sleep better (progesterone has GABAergic activity and is genuinely sedating at physiological doses), feel less anxious, experience some mood stabilisation. These are real effects. Progesterone is not a benign supplement to be dismissed.
But it does not address the underlying driver. The adrenal demand for cortisol continues. The pregnenolone diversion continues. The HPA axis dysregulation continues. And the question of whether exogenous progesterone is being converted to cortisol in the periphery — which it can be, particularly in states of high adrenal demand — adds a layer of complexity that is rarely discussed in the bioidentical hormone literature.
This is the conversation that doesn't happen often enough: what is the stress load doing to this person's steroidogenesis pathway, and is giving them more progesterone going to compound a problem rather than solve it?
There is a broader principle here that I think is worth stating explicitly, because it runs counter to the reflex of modern functional medicine which tends toward the question of "what's low and how do we raise it."
Hormones don't become deficient randomly. The body regulates them with extraordinary precision. When a hormone is low — whether that's progesterone, testosterone, thyroid hormone, or oestrogen — the question worth asking first is whether the body is making a deliberate downregulation decision and, if so, why.
Sometimes the answer is straightforward nutritional: the substrate for synthesis is missing. Low cholesterol, inadequate zinc, B5 deficiency (essential for adrenal steroidogenesis), vitamin C insufficiency — these are correctable inputs that constrain output. If progesterone is low because the adrenals don't have adequate B5 to drive the relevant enzyme reactions, then supplementing B5 is the intervention, not supplementing progesterone.
Sometimes the answer is demand-driven: the body is making less of one hormone because it needs more of another. The pregnenolone steal is one example. Thyroid hormone being suppressed by chronic cortisol elevation (via inhibition of T4 to T3 conversion and upregulation of reverse T3) is another. The body isn't failing — it's adapting.
And sometimes — this is the most clinically interesting category — the deficiency is protective. Low oestrogen in the context of active oestrogen-sensitive pathology. Low testosterone in the context of prostate pathology. The body may be producing less of a hormone specifically because elevated levels of that hormone would be harmful. In these cases, supplementing toward a number on a lab report is not just unhelpful but potentially dangerous.
None of this means bioidentical hormone supplementation is wrong. It means it requires context — which is another way of saying it requires investigation before intervention.
Ray Peat — the biologist and health researcher who died in 2022 and whose work remains influential in certain functional medicine circles — had a number of positions that are not in the mainstream but deserve serious engagement.
Peat is not everyone's cup of tea, and some of his dietary prescriptions (saturated fat as overwhelmingly beneficial, polyunsaturated fats as categorically harmful, milk and orange juice as central foods) don't map onto clinical reality in the way his theoretical framework might suggest. His followers sometimes apply his principles with a rigidity that he himself may not have intended.
But his underlying physiological thinking — particularly around oestrogen, progesterone, thyroid, and the relationship between energy metabolism and hormone balance — is more clinically grounded than his reputation in conventional circles suggests.
On progesterone specifically, Peat made several arguments that hold up clinically:
Progesterone as anti-oestrogenic. Peat was emphatic that progesterone opposes oestrogen's effects at the cellular level — promoting differentiation over proliferation, reducing water retention, opposing some of oestrogen's inflammatory effects. This is well-established biochemistry. The clinical relevance is that a woman with symptoms of oestrogen dominance — heavy periods, breast tenderness, fluid retention, fibrocystic changes — often has not too much oestrogen in absolute terms but insufficient progesterone to balance it. The ratio matters as much as the absolute levels.
Progesterone as neuroprotective. Peat was ahead of the mainstream in emphasising progesterone's role in the nervous system — in myelination, in GABAergic signalling, in reducing neuroinflammation. The research on progesterone as a neuroprotective agent in brain injury has subsequently grown significantly. The clinical implication: progesterone deficiency in perimenopausal women may contribute more to the cognitive and mood symptoms of that transition than is generally recognised.
Thyroid as central. Peat viewed adequate thyroid function as foundational to everything else — hormone synthesis, energy metabolism, gut motility, immune function. His position that subclinical hypothyroidism is dramatically underdiagnosed and dramatically consequential is one I share. The functional thyroid picture — looking at free T3, reverse T3, and antibodies rather than TSH alone — is the clinical approach that Peat argued for decades before it became more common in integrative practice.
The oestrogen excess problem. Peat was deeply concerned about oestrogen excess — from exogenous sources (environmental oestrogens, synthetic HRT), from poor oestrogen clearance (liver and gut dysfunction), and from inadequate progesterone to oppose it. He saw oestrogen excess as a driver of stress physiology, not just a hormonal imbalance in isolation. The research on the estrobolome, on beta-glucuronidase, and on oestrogen metabolism — which has grown substantially since Peat's early writing — provides mechanistic support for many of his concerns.
The clinical complexity that Peat's framework doesn't fully account for is individual variation — which is, of course, the central argument of this practice.
Peat's dietary recommendations — high saturated fat, low polyunsaturated fat, high simple carbohydrates from fruit and dairy — work well for some people and clearly don't for others. The metabolic phenotype that thrives on this approach is real, but it is not universal. Someone with significant insulin resistance, dysbiotic gut microbiome, or APOE4 genetics will not necessarily respond to a high-fruit, high-dairy dietary approach in the way Peat's framework predicts.
More significantly, the progesterone supplementation that Peat advocated — topical progesterone, relatively freely applied — makes sense in the context of his broader theoretical model (progesterone as safe, anti-stress, broadly protective) but misses the individual clinical question of what the progesterone will be converted into and how in any specific person. Without a DUTCH Plus showing the metabolite picture — what happens to progesterone downstream, including its conversion to allopregnanolone and its potential partial conversion toward cortisol — you don't fully know what you're doing.
This is not a criticism of Peat's underlying biology. It's an argument for testing before supplementing — which Peat himself didn't emphasise sufficiently.
When a client comes to me asking about bioidentical progesterone — often because they've read about it, or been prescribed it elsewhere, or because perimenopause is making their life difficult — the clinical assessment I want to do before anything is prescribed includes:
DUTCH Plus — the complete hormone picture. Not just progesterone levels but the full metabolite cascade: how oestrogen is being metabolised (2-OH vs 4-OH vs 16-OH ratio), whether cortisol and DHEA show evidence of pregnenolone steal, what the androgens are doing, and what the overall stress hormone picture looks like. This is the map. You don't navigate without a map.
GI-MAP — because oestrogen recirculation via beta-glucuronidase is a gut microbiome story. If beta-glucuronidase is elevated, oestrogen that should be excreted is being reabsorbed. If the microbiome is dysbiotic, the estrobolome is disrupted. Hormone balance and gut health are not separate departments.
Blood chemistry — including thyroid (TSH is not enough — free T3, reverse T3, TPO antibodies), fasting glucose and insulin (insulin resistance affects sex hormone binding and clearance), liver function (the liver is where most oestrogen metabolism happens), and inflammatory markers (chronic inflammation disrupts steroidogenesis at multiple points).
With that picture in hand, the conversation about bioidentical hormones becomes specific rather than generic. Is the progesterone low because of chronic HPA activation? Because of poor nutritional substrate? Because of inadequate thyroid function driving down overall steroidogenesis? Because the monthly cycle is shortening and the luteal phase is truncating? Each of these has a different primary intervention, and progesterone supplementation may or may not be appropriate alongside it.
Investigate the system before supplementing the hormone. The DUTCH Plus gives the full metabolite picture — not just what's low but what's happening upstream and downstream. That's the difference between replacing a number and understanding a physiology.
The distinction between bioidentical and synthetic hormones is real and clinically meaningful, though sometimes overstated in marketing.
Bioidentical hormones have the same molecular structure as the hormones the body produces. Synthetic progestins — medroxyprogesterone acetate being the most studied — do not. The difference matters because synthetic progestins do not have the same receptor binding profile, the same neurological effects, the same conversion pathways, or the same safety profile as progesterone. The Women's Health Initiative data showing increased breast cancer risk with combined HRT used a synthetic progestin, not bioidentical progesterone — a distinction that is still not consistently communicated to patients.
Micronised progesterone (Utrogestan in the UK) is bioidentical and has a meaningfully different safety and tolerability profile from synthetic progestins. This matters. If a woman is going to take progesterone, bioidentical is the better-evidenced choice.
But "better than the synthetic alternative" is a lower bar than "the right intervention for this person at this time." That determination requires the full clinical picture — which is where this conversation always returns.
Bioidentical hormone therapy has a genuine place in clinical practice — particularly for women navigating perimenopause, where the symptomatic benefit of appropriate progesterone support can be significant and the evidence base is more robust than is often acknowledged in conventional settings.
But the most important word in that sentence is appropriate. Appropriate means based on a full understanding of the hormonal picture — the metabolite cascade, the stress axis, the gut, the thyroid, the nutritional substrate. It means asking why before asking how much. It means not treating a DUTCH result as a shopping list and a prescription pad as the solution.
Ray Peat would have agreed with the underlying biology here, even if his prescriptions sometimes ran ahead of his diagnostics. The body is a system. Hormones are signals within that system. Understanding the signal before you amplify it is not caution for its own sake — it is the beginning of actually doing something useful.
The DUTCH Plus is the test that maps the full steroidogenesis cascade — not just what's low but why. It's part of the TDG Five-Test Programme, or available as a standalone investigation.
Explore the DUTCH Plus