Visual bias: The pituitary gland in HPT axis diagrams

Too many diagrams focus on the “HPT axis,” in which the Hypothalamus, the Pituitary, and Thyroid gland are the biggest icons.

Take for example this diagram from Ortiga-Carvalho’s chapter in a physiology textbook.

The huge, super-ballsy pituitary. Seriously?

In diagrams like these (this is not the only such pictorial), the truly pea-sized TSH-secreting pituitary gets blown out of proportion.

It’s now a masculine, two-lobed blob that dangles over the thyroid like a master commanding his passive, smaller-sized servant.

Pituitaries don’t normally get this large in relationship to the thyroid gland, so this is as physiologically incorrect a diagram as one can be. In a physiology textbook, nonetheless.

The condition of “Pituitary Hyperplasia,” or pituitary enlargement, indicates a serious pathology. According to Radiopedia, an encyclopedia for radiologists,

“The upper limit of normal pituitary height varies with age and gender: infants, children: 6 mm; males and postmenopausal women: 8 mm; young menstruating females: 10 mm; pregnant/lactating women: 12 mm.

Non-physiologic pituitary hyperplasia is commonly caused by an end-organ failure such as hypothyroidism, Addison disease and neuroendocrine tumors. Medications such as estrogen, GnRH analogs and antipsychotics can cause or exacerbate pituitary hyperplasia.”

– Radiopaedia.org

That’s nice. In this quotation, hypothyroidism is given the honor of being “end-organ failure,” rather than just being a biochemical blip treated with a levothyroxine trip.

Is there any symbolic reason why the pituitary is so inflated in this model, such as its magnitude of hormone secretion?

No, there’s no reason at all.

• The TSH hormone is one of many hormones secreted by the pituitary, just a small fragment of its role in the human body.
• In healthy human beings, the TSH secretion is a gentle conversation within 0.3 and 4.00 mU/L, not a screaming high number like 10 or 150, seen in untreated hypothyroid individuals.

Do you think this ponderous pituitary is larger than it would be in a hypothyroid patient with a TSH of 150? Ask a radiologist.

Hormones stuck in perpetual feedback loops

In these hyperplastic, hackneyed diagrams, the hormones T4 and T3 are reduced to tiny letters on thin arrows flowing between the glands like puny messengers.

Gland-centric views make the hormones seem to exist merely to enable the feedback loops amongst these glands and keep them running.

There is no outside arrow signaling to the hypothalamus and pituitary, but in real life there is. How about the effects of fasting and overeating on leptin levels? How about seasonal change in a harsh climate? Pituitary gland says

“Oh, what’s that? You’re saying I have to start pushing the thyroid gland harder to secrete more T3 because it’s getting colder outside? Sorry, the visual diagram says I can’t accept external inputs. I’m overruled by this stupid negative feedback loop in this picture.”

– Sincerely, Your pituitary gland.

It represents a self-enclosed system, isolated from the rest of our bodies, the very opposite of the physiological reality of the importance of these hormones to every organ’s health.

This quote from the same physiology textbook chapter, for example, diminishes T3’s primary role to this interglandular conversation:

“T3 is responsible for several critical biological phenomena, such as providing negative feedback for thyrotropin-releasing hormone (TRH) and thyrotropin (thyroid-stimulating hormone, TSH) synthesis at the hypothalamus and anterior pituitary gland, respectively.”

(Ortiga-Carvalho et al, 2016)

Hello, what about T3’s role in preventing heart failure and mental illness?

How about the T3 refill we get when TSH rises high during recovery from critical illness like a stroke? That refill that basically saves our lives from non-recovery from “Low T3 syndrome” induced by the acute phase of illness?

Not in this graphic. In this graphic, the three glands are stuck in a loop in which their main job is to keep each other going. They’re not interested in saving your life by restoring T3 hormone supply to your heart or your brain.

Hormone replacement vs. gland function replacement

Graphics like these also lead people to think, mistakenly, that they can simply “replace” the thyroid gland with a thyroid pharmaceutical containing a static amount of hormone each day.

Moreover, the standard “replacement” includes 0% of the most potent thyroid hormone, T3.

There is no such thing as even a fraction of thyroid gland tissue that secretes 0% T3 in this HPT axis diagram, so what gives?

In our societies, we see a non-physiological drive to make the flowchart for TSH “screening” apply equally, without any edits, to TSH-based “monitoring” of hypothyroid treatment. It’s a sort of monitoring-by-“reverse-screening” logic. If you don’t show up on a screening test anymore, you must be cured of hypothyroidism.

This reverse-screening logic only works if your TSH can be trusted to judge the efficacy of your therapy beyond its own tissues. It is based on the assumption that TSH is equally reliable when replacing a T4-T3 converting end-organ with a pill that can’t convert its own T4 to T3.

The belief of pituitary invulnerability is promoted by the removal of tests, other evidence, that could raise doubts about the TSH as the primary judge of thyroid status in therapy. This is why we have penny-pinching campaigns to cancel cheap $9 FT3 and $12 FT4 thyroid hormone tests, discourage even cheaper Achilles reflex testing, and utterly dismiss symptom scoring during thyroid hormone therapy.

There is no room for an evidence-based “altered HPT axis in therapy” diagram because the institutions of thyroid health care will not accommodate their flowcharts and treatment policies to fit the altered thyroid hormone economy.

The skewed HPT axis in therapy

The HPT axis can become progressively skewed in thyroid disease and therapy. In standard LT4 monotherapy, the TSH-FT3 disjoint deepens as thyroid tissue is lost. In addition, TSH can be directly lowered at the pituitary by TSH-receptor-stimulating antibodies in Graves’ Disease patients, despite low or normal thyroid hormone levels after a total thyroidectomy. Up to 10% of Hashimoto’s patients have measurable Graves’ Disease antibodies.

Now consider that some healthy people require the maintenance of both T3 and T4 in the upper parts of their reference ranges over days, weeks, and months, according to research showing the stability and narrow ranges of these hormone levels.

Why is a significant distortion in HPT axis biochemistry induced by thyroid loss and thyroid therapy not alarming? Why is has this illogic been ingrained for so many decades?

Oh, here’s why. It’s a biochemical bias toward believing the vote of pituitary TSH at the expense of FT3. It’s only the loss of the most potent and essential thyroid hormone, T3.

Why can’t we just let the TSH number fall where it may during thyroid therapy, while

• permitting FT3 to rise mildly higher to compensate for lower FT4 in T3-dominant therapies,
• permitting FT4 to rise mildly higher to convert to enough FT3 in T4-dominant therapies, and
• cross-checking euthyroid tissue thyroid status with other biomarkers of thyroid hormone response in the heart, kidney, liver, digestive system, muscles, and ligaments?

Today’s pathology of medical thinking prioritizes a single pituitary hormone over the more direct measure of the supply and ratio of both thyroid hormones in blood. It is a medical ideology that would rather believe TSH more than the evidence of T3 signalling in other organs.

This mode of thinking can be partly attributed to the subliminal, gut-level persuasion in the pituitary-dominant visual diagram, which eliminates other organs’ T3-sensitive biomarkers from view and lacks any hint that TSH can be biased by signals like leptin, glucocorticoids, TSH receptor antibodies, inflammatory cytokines, and so on.

Let’s make an honest HPT axis for thyroid therapy.

Many hypothyroid patients still have some functional thyroid tissue, but let’s take the example of the most extreme situation — a person after a Total Thyroidectomy (TT) or someone with autoimmune thyroid disease whose thyroid has fully atrophied or cells have been fully fibrosed by antibody attack.

Many types of thyroid medication and combinations exist, but let’s take the most common therapy used, levothyroxine (LT4) monotherapy, with no T3 provided from medicatino.

If you’re using standard levothyroxine monotherapy to “replace” a healthy thyroid’s secretions, you have to erase the T3 arrow coming from the pill bottle, and make its T4 arrow supraphysiologically thicker.

Moreover, you have to include the GI tract in the model. A healthy thyroid infuses T4 directly into the bloodstream. But the pill’s infusion into the bloodstream is mediated through that organ system. Its T4 can’t reach the hypothalamus or pituitary without going through GI tract. It’s now part of the HPT axis.

Next, you have to erase or alter another arrow coming from the pituitary down to the pill bottle. There is no physiological need for thyroid stimulating hormone to stimulate a daily hormone pill. Normalized TSH not going to help induce optimized T4 or T3 as it would induce in a real thyroid gland.

You must now erase the green TSH arrow from the pituitary to the pill bottle.

Now, to be 100% medically accurate, you must draw a new green arrow pointing form the pituitary outside the patient’s body to the medical professional looking at a diagnostic testing flowchart modeled on pre-therapy thyroid function screening.

To be honest about what’s different in this HPT axis, you have to add some annotations about some of the differences in T3 secretions, FT3:FT4 ratios and the local T4-T3 conversion rates in the hypothalamus and pituitary gland.

What do you think of the edited HPT axis diagram for the person with no thyroid?

Sure, this diagram is ridiculously complex now.

Welcome to the complex reality of thyroid hormone therapy.

You’ve got interferences on every side, from

• the hormone therapy recommended vs not recommended by committee, to
• the highly variable GI tract absorption depending on what you ate 2 hours ago, and whether you have enough stomach acid, to
• the medical guidelines for TSH that keep their own guidelines perpetually validated in a perpetual cycle of TSH-LT4 self-validation.

The inequities between thyroid-healthy people and LT4-treated people should make you wonder if the HPT axis is really the same HPT axis even from the pituitary’s point of view.

What do you think this person’s pituitary TSH is prescribing? Let’s look in Pilo’s 1990 article for someone of their age and sex.

• Would it be 15% T3 and 85% T4 for Mary?
• Or how about 30% T3 for Joseph, because he’s a 31 year old male?

Do we really think hypothalami and pituitaries are that selfish that they only care about the health of their own tissues?

• What levels of TRH and TSH might they rise to if they had undosed freedom to rise higher?
• What would the TSH become if the body was not overburdened with all that extra T4 in blood, which converts less efficiently in most tissues when it’s higher in reference?
• Does the pituitary really know that Mary’s T4 isn’t getting well converted in other tissues that express more DIO3 and DIO1 enzymes than her pituitary tissues do?

Put the pituitary in its place.

The pituitary TSH is merely the servant of a living thyroid gland. A living thyroid gland. Not a pill.

The pituitary hasn’t got the memo — it does not know the thyroid gland has failed because we keep tricking it with drugs.

We’ve turned the hypothalamus and pituitary into a dose-monitor of a static T4:T3 ratio that we prescribe based on our biased interpretations and preferences. Validating our medical decision making is a function TSH is poorly designed to perform.

TSH never perfectly adjusts the LT4 monotherapy patient’s dose because TSH is always prescribing thyroidal T3 in health.

In health, TSH always induces an adjusted T4:T3 ratio to help the entire body, not just a new T4 dose that makes hypothalamic and pituitary tissues well-supplied with T3.

A negative feedback loop without a functional positive feedback loop is like one hand clapping.

But we’ve forced the other hand to clap by routing TSH through decades of paint-by-number thyroid health care policy and the doctor’s dogma-programmed fear-addled brain.

Pituitary power has been artificially extended past its expiry date by human-made policy. In some patriarchal societies of the past, women were transferred from their father’s authority to their husband’s authority. At least they got some freedom in widowhood. In our model, the thyroid patient is never freed from TSH tyranny, well past the date at which TSH could beneficially regulate thyroid hormone supply.

The hormone-centric view

So, let’s shift more than just the visual accuracy and visual symbolism. Let’s shift the narrative.

The thyroid hormone journey is full of drama, beauty and peril. It’s complex enough to deserve its own story.

The thyroid hormones T3 and T4 are the true heroes of the hormone-centric narrative.

Mainly, it’s the queen of all hormones, T3, whom the thyroid and pituitary glands must serve and protect, because it’s absolutely essential to life and health. Its supply and metabolism has to be well-controlled so that things are working properly. There has to be just the right amount of T3 created or supplied in the right places, no less, no more.

Conclusion

Because of images that distort the dominance of pituitary TSH in treated hypothyroid people, it has become impossible to separate the idea of excess thyroid hormone and suppressed or low TSH.

But the separation of “hypothyrotropinemia” (low TSH) from “thyrotoxicosis” (excess thyroid hormone) is necessary in thyroid therapy, where they do not go hand in hand.

In thyroid therapy, the low-T3 health risk signified by the TSH-T3 disjoint overrules the demand for perpetual pituitary dominance.

Is a person with high-normal FT4 and low-normal or low FT3 truly “euthyroid” if the normal TSH can’t compute the abnormal hormone ratio?

How healthy can a low FT3:FT4 ratio be if even people with healthy thyroids are at higher risk of death and morbidity under such ratios, despite a normal TSH, in chronic illnesses such as heart failure, renal failure, neurological disorders and cancers?

Let’s ask what’s going on at the molecular level, outside the 3-gland conversation, as hormones activate receptors in cells.

Example, Patient #1, Sarah. Let’s take a person after thyroid cancer, who is undergoing TSH-suppressive therapy but whose T4 and T3 are in normal range. They have no signs of thyrotixicosis. Does the mitochondrion in her cells getting a T3 or T2 infusion say “oh no! I can’t admit entry to you yet, dear T3 and T2, because this cell I’m floating in has not had any TSH stimulation in a long while! If I let you in, I fear that I’ll instantly become thyrotoxic without a TSH molecule on my host cell!”

Example, Patient #2, Mark. Here’s a person who has just had a heart attack 1 week ago and is in the Intensive Care Unit, and doctors are worried because T3 is still low (a rare, courageous doctor insisted on checking Total T3 despite the anti-testing policy, and they know that FT3 will be inflated by heparin dosing, so they ordered TT3), and now TSH and T4 are falling, too. That indicates an even worse prognosis! Does his heart muscle suffering from hypo-triiodothyronemia say to the T3 molecule trying to get in, “sorry, T3, but I can’t risk admitting you to my cells until I first get more of my TSH receptors activated.”

Are there likely to be many TSH receptors on heart muscle cells? You’ll learn more if I don’t tell you and you take the effort to look it up yourself.

• Look up the TSHR gene expression in the Human Protein Atlas — see the bar chart under RNA expression, the consensus data set.
• Then compare it to the consensus tissue RNA expression data set for the THRA gene, which regulates the T3 receptor types dominant in heart tissue.

Finally, Patient #3. Here’s your grandma or your aunt. Normal TSH but not so normal T3:T4 ratio. Does her failing kidney, inducing chronic low T3 levels in her LT4-treated body say, sorry, I can’t accept any T3 dose donations. Natural recovery from low T3 mandates that my TSH must first rise above normal range and stimulate a T3 refill from my thyroid gland. Oh what’s that? your aunt’s thyroid gland died long ago from autoimmune Atrophic Thyroiditis and is now the size of two flattened raisins? Then I guess we’re hooped. Isn’t it strange that scientists have never studied the death rates of thyroidless people on TSH-normalized LT4 monotherapy in kidney failure?”

Call to action

Let’s cure the disease of visualized pituitary hyperplasia that is infecting textbooks and medical office posters.

Let’s put an end to this distorted, gland-centric pituitary puffery in medical artwork.

It might go a long way to helping people stop fantasizing that the pituitary’s role in the HPT axis is identical in a thyroid-healthy population and a thyroid disabled, thyroid-hormone-treated population.