It’s good for skin! It’s good for bones! It’s good for hormones! It’s good for immunity! It prevents certain cancers!

Seriously Vitamin D, would you stop stealing the show? Leave a little room for the rest of the alphabet. It’s getting a little annoying.

Everyone is being swooned by you and all the other letters are feeling a little resentful. That is not how you make friends, D. But I guess if you want fame and fortune, you gotta make yourself known.

So Doc, just tell me: “How much should I be taking? I know it’s the one supplement that everyone needs to take. Even with diligent internet searching, all signs point to positive.”

Well if your doctor happens to be a scientist they most certainly would not agree with you. Not because it’s incorrect, but because we’d best be cautious with anything that stores in your body and acts like a hormone on every cell and gene in your body.

(Does anyone remember what a godsend estrogen-only was for menopausal women? Look how that turned out.)

The deeper we go with our meddling, the harder it is to backpedal out. Cellular & genetic change is not for the faint of heart. And diving into Vitamin D research is quite overwhelming too.

But I am a courageous clinician, so I will investigate.

Let’s get introduced. Vitamin D is known as the “sunshine vitamin” or rickets preventative factor.

From here on in I’ll call him Hormone D (we all know he’s been posing), so let’s not get carried away thinking of it like a normal dietary nutrient. He’s been all over the news so you may know bits and pieces of his promiscuous relationships already. But it is always best to start at the beginning; pick and choose from what you don’t know.

What is Rickets?

Rickets occurs when the epicartilage of the long bones grows without replacement by bone matrix and minerals, and bones soften (Osteomalacia) as a result of inadequate deposition of Calcium and Phosphorus in the bones (1).

It is visible because of enlargement of the wrists, ankles, & knees. The long bones of legs start bowing out as the knees knock in (1). There is also a classic sign of costochondral beading, which is basically knobby-ness where your ribs meet your breastbone (1). They called it the rachitic rosary of ribs – because it looks like a row of rosary beads? Maybe yogis could call it a malnutrition mala? That sounds weird. But so does rosary.

In the 1800s, Rickets was rampant and a man with dogs discovered that Cod Liver Oil prevented it. Scientists thought the key was Vitamin A, but when they tested it they discovered there was something else in that CLO that was doing the job. They called it the anti-rachitic factor and assumed that because it was in oil, it must be a fat-soluble vitamin (2).

In the 20s & 30s, a clear connection was found between this factor and sunlight on skin. It was made clear that this was not a necessary dietary nutrient, but a necessaryirradiation of skin cholesterol (2,3). All forces were working against Lil’D in nomenclature because nutrition was a developing science in the 20s. The naming of  nutrients overrode, and this one was named Vitamin D.

The rationale was that plants make a form of Vitamin D from their cholesterol too, and all animals make it and we (sometimes) eat livers of said animals, and it is easier to classify into boxes we already know of, so it conveniently became a Vitamin (2). I would liken it to saying that Thyroid Hormone is a vitamin because thyroid deficiency is helped by eating thyroid glands. Eating an animal product works, but it’s supplying a hormone not a vitamin.

In the 1980s, the mechanism and sequence of synthesis and metabolism was outlined. Science takes time. Patience, little feather

First, All the names:

There is D2 – made from irradiation of plant cholesterol. Structurally, 1 carbon & 1 double bond difference from human-made D3.

7-Dehydrocholesterol: AKA 7-DHC, In the skin – made from cholesterol in the sebaceous glands of the skin.

There is Pre-D3 – What is formed after irradiation.

THEN, there is D3 (AKA D3, Cholecalciferol: (the first conversion from Pre-D3)

THEN, there is D3 plus: AKA, 25 (OH) D3, Calcidiol – (diol, for the 2nd conversion)

THEN, there is D3 plus plus: AKA 1,25 (OH)2 D3, Calcitriol. (triol, for the 3rd conversion)

Hormone D is my term for all of these lumped together, otherwise I’ll use the conversion names.

Calcitriol (D3 plus plus) is the active form of Hormone D. Tightly regulated. You do not take calcitriol as a supplement. It's a medication and should be monitored. 

Cholecalciferol (D3) is the common OTC Vitamin D.

Other important names:

Vitamin D Binding Protein: AKA VDBP, also known as trancalciferin, made in the liver.

Parathyroid Hormone: AKA PTH – partners in crime with Hormone D. The active form of D3 is only triggered if PTH tells it to form.

Solar Zenith Angle (SZA): angle between your local vertical; (zenith) and line from the observer to the sun. (The angle of sun on your body)

As you can tell from the one consistent syllable – Hormone D is all about Calcium regulation, whether that means Calcium in bones, genes, muscles, nerves, cells, hormone signalling, my research shows it is always related to Calcium’s role in those reactions. Keep that in mind.

Conversion 1. How we make it:

We make 7DHC from cholesterol. UVB rays beam down, irradiate the 7DHC, and break a bond. Wavelengths of UVB between 290-315 nm are the only lengths that can do this. Our atmosphere normally allows for it (3).

At this point, it’s still not considered Cholecalciferol yet – It is called pre-D3. Some of the 7DHC turns into other sterols but the one we turn our attention to most is pre-D3. Next we have to warm it up and only then can pre-D3 make the necessary chemical change to push this hormone into circulation (4). Body temperature is the perfect temperature for this change. A couple of hours of body warmth and voila,Cholecalciferol (D3) is made (1).

  • Cholecalciferol mostly (85-88%) binds to VDBP (1, 5).
  • 12-15% binds a blood protein called Albumin(5).

Surprisingly to me, only 2% of circulating VDBP is actually even involved in Vitamin D acquisition. The other 98%  is doing other things in the body; like scavenging actin released from cells and activation of macrophages and osteoclasts (6)

What affects our ability to make it (3):

  • A 5% decrease in atmospheric O3 = 15% increase in monthly UVB. This means ozone depletion is technically positive for our Vitamin D levels. Egad. Ethics.
  • Thick cloud can reduce conversion to 1% of what you would convert in clear skies.
  • It is affected by your town’s atmosphere, O2, Nitrogen, aerosols, water vapour, particulate pollutants, clouds.
  • Black carbon can decrease conversion up to 5% in urban environments.

Maybe its awash. Pollution & ozone depletion = same conversion.

  • Also, there’s that SZA: Small SZA = High UV; larger SZA = Lower UV.
  • Higher UV = bad for melanoma; Higher UV = good for Hormone D. What a conundrum.

Statistics show that north of 35, we get anywhere from 6-8 months maximum per year, to make the recommended daily of Hormone D. The rest has to come from stores. Below 35, people can make it all year round (3). (P.S. Apparently, Canada we are SOL from November to April – Why hasn’t anyone studied us as a population yet?) Does that reflect in osteoporosis rates and fractures? No idea. Some have made the correlation between colorectal cancer rates and these latitudes, but that’s all I’ve seen.

  • In addition, there’s clothing, burn scars, sunscreen & melanin – our dark skin cells, our innate sunscreen. Melanin absorbs UVB rays and thus competes with 7-DHC for photons (1, 3).

When we take it orally (called D3 – Cholecalciferol or D2 Ergocalciferol), what happens to it:

First: There has been a movement against using D2, as some have said it doesn’t convert as easily to Calcidiol as D3. I will present the details of cholecalciferol for ease of typing, but this does not mean that D2 is not effective. Ergo, ergo should be considered to have similar routes. 

Absorption of cholecalciferol from the gastrointestinal tract is dependent on fat absorption (1, 6, 7).

It is rapidly absorbed in the beginning of the small intestine (the duodenum) but the largest amounts are absorbed in the distal small intestine (the ileum) (1). Risk of malabsorption occurs in celiac, biliary obstruction & chronic pancreatitis. In these conditions, absorption falls to between 18-50% of oral dose (3). Malabsorption is also seen in Liver failure, Cystic Fibrosis, Crohn’s, Gastric bypass surgery, use of bile acid binders. The deficiency in all of these conditions are correlated with fat malabsorption (3).

Distinct from skin transport, most gastrointestinal cholecalciferol is incorporated into chylomicrons, instead of VDBP. (6). Over time, cholecalciferol will change over to VDBP, or go to the liver for its 2nd conversion (7).

Major differences between creation and consumption:

  • Chylomicron transport increases the likelihood of deposition in adipose and muscle tissues before reaching the liver (1,9). The liver will quickly uptake what is left in the chylomicron remnant, and on it goes to be converted(7, 10)

  • VDBP transport  increases the likelihood that Cholecalciferol will be delivered to the liver for conversion (1).

  • Radiated Hormone D peaks 24-48 hours after irradiation and decline back to pre-exposure levels within 7 days (3).
  • Oral Hormone D produces an increase in blood concentrations of vitamin D more quickly than cutaneous synthesis, reaching peak concentrations at 10 hours and returning to baseline by approximately 2 days (11).

Now, onto Conversion 2. In the liver:

Mixed function oxidases (cytochrome p450 hydroxylases) in the liver are just waiting to convert cholecalciferol into calcidol. In the mitochondria of cells, 25-hydroxylase gets to work and converts (1). The efficiency of 25-hydroxylase is related to Hormone D concentration and metabolism, ie; more efficient in periods of Hormone D deprivation than when sufficient (12). This enzyme is mostly in liver, but also in lungs, intestine, kidneys (1).

There is a restricted physiologic window of 75-220 nmol/L (that’s a big window) which determines the efficiency of  hydroxylase in converting cholecalciferol to calcidiol (3). 

The rate of increase of serum 25 D3 for oral dose is inverse to starting levels (3):

  • If you have low levels to start  (<50 nmol/L), the conversion is 1.2 nmol/L for every 40IU consumed daily.
  • In severe deficiency (<10 nmol/L) conversion is 3.45 nmol/L for every 40IU consumed daily.
  • At high levels (>70 nmol/L) rate is 0.7 nmol/L for every 40IU consumed daily.

Heaney posits that in sufficient states, ~ 40 % oral cholecalciferol converts to calcidiol and that “the remainder is is building up, both in blood and in storage depots (presumably, fat depots)” (12).

Like most other vitamins, “Concentration of serum calcidiol in response to input of vitamin D3 in humans is biphasic: a rapid increase occurs at low vitamin D3 concentrations and a slower response occurs at higher concentrations” (12).

Once it is converted, Calcidiol is released into blood. Calcidiol is the main form of Hormone D that we find in the body. It reflects body status and is transported by VDBP. Small amounts remain in the liver, or get taken up by tissues. Blood is the largest pool, and its half-life is 10-21 days (1). When deprived of Hormone D, this pool is depleted, and Cholecalciferol is released from skin & adipose to begin the conversion process again.

Important reminder: As far as we know, Calcidiol is not biologically active unless at very high non-physiological levels.(3)

Jees louise. It’s not even active yet? This a high maintenance vitamin. Oh right. It’s not a vitamin. It’s a regulated and responsive hormone That’s why it’s so complicated. Stay with me.

The final frontier: Calcitriol

The 3rd and final conversion of Hormone D, is via a mitochondrial enzyme in kidney tubules.  VDBP-Calcidiol complex is taken up by specific receptors in the kidney tubules, and Calcidiol easily dissociates to be available for conversion (1). 1-α-hydroxylase is responsible for the conversion of Calcidiol into Calcitriol – which is the active form of Hormone D. It is tightly regulated. This enzyme is mostly in the kidney, but also found in macrophages, skin, intestine & bone (1).

It is increased by (1, 3):

  • low blood calcium concentrations
  • PTH signalling
  • low Calcitriol concentrations
  • low Phosphorus concentration.

It is decreased by:

  • Dietary PO4 (impairs conversion) not phosphorus, but phosphates
  • Sufficient calcitriol

Once formed, Calcitriol is easily transported to reach tissues and is easily released. It quickly binds to Vitamin D receptors (VDR). It does its job, quick stix.

Its main modus operandi is to make sure blood calcium is maintained. It will stop at nothing. The three ways Calcitriol does this, in order of priority:

  • Increase Calcium absorption in the gut
  • Decrease Calcium loss from the kidney
  • Pull Calcium from bone – spearheaded by PTH

It does all these things by acting as a gene regulator, by stimulating certain proteins, by differentiating osteoclasts & by collusion with other organs and hormones.

If blood calcium levels are above normal, Calcitonin (a hormone from thyroid cells) stimulates bone mineralization. Looks like your throat is more involved with your bones that you thought.

When both Calcitriol & Calcium are high, they can cause PTH to lay off and decrease. 

In addition to all this calcium regulation, Calcitrol reduces proliferation in fibroblasts, keratinocytes, lymphocytes & abnormal cells (intestinal cells, lymph, mammary, skeletal, skin); which is why so much attention is being brought from a cancer prevention point of view (1).

Excretion: excreted in bile; over 70% excreted via feces (1), but excess D3 is taken up by adipocytes, subcutaneous tissue or omental tissue (which prolongs the half life to 2 months)

Adequate Intake: 200IU; 5ug. This is enough to prevent the ghastly disease of rickets. It can be obtained by sunlight, daily. 10 minutes of summer sun on face and hands gives a caucasian american 400IU. Plan accordingly. (1)

Toxicity: When synthesized by skin, there is no risk of excess conversion. 

Over supplementation of D3 can increase calcidiol concentrations, because the window of regulating production is large. Toxicity has been seen at levels over this window (~250-750 nmol/L) (10).  Calcidiol may stimulate some of the same actions as calcitriol, at high levels (3). 

The number of what should be taken everyday as a supplement is still controversial, so I won’t put those numbers in here. In 2010 the Recommended Daily was increased to between 400-800 IU depending on life stage.

You know what’s really annoying about studies? Depending on the author, they use different units. All the time. I have translated them below, and switch back and forth, so that you can learn.

Labs for Calcidiol (Our “storage Vitamin D”):

deficient <20 ng/ml = <50 nmol/L

insufficient 10-20 ng/ml = 25-50nmol/L

adequate 20-30 ng/ml = 50-75 nmol/L

high 30-50ng/ml = 75-125ish nmol/L

Other Interesting facts:

  • Doses over 10 000 IU for several months cause calcinosis (soft tissue calcification in the kidney, heart, liver, blood vessels), hyper phosphatemia, hypertension, anorexia, nausea, weakness & renal dysfunction (1).

  • It was observed that a single dose 100 000 IU, with no vitamin D supplementation or dietary sources afterwards, will decrease to 75-80nmol/L after 84 days, with no toxicity symptoms (13).

  • For other health benefits – as in cardiovascular health indicators, insulin resistance, colorectal cancer prevention –  blood levels of Hormone D & Calcium would need to be high enough to suppress PTH. This situation has found Calcidiol at 75-80 nmol/L (30-32 ng/ml)(13). Some studies show that between 20-30ng/ml is actually the enough to suppress PTH, and higher gives negligible benefit (14, 15).
  • After a certain window of calcidiol blood levels, no benefit was seen with falls, fractures, cardiovascular indicators , insulin resistance (14, 15, 16). In fact some studies show that harm may be occurring, even if is not considered toxicity  (14,15).
  • Estrogen increases the activity of 1-α hydroxylase (Calcidiol –> Calcitriol) (17). Estrogen also increases the activation of the vitamin D receptor (17).
  • Upon supplementation in hormone D deficient men, one study showed that testosterone levels have been shown to increase (18). But then two years later another study showed there was no association (19). Except in the 2nd study they tested males with adequate levels of Vitamin D (19).

There you go. No conclusion. Just like that. It is wise not to conclude on an emerging topic.

Now: Questions I have about Vitamin D. Because, you can't be a scientist without questions.

  1. For illness beyond bone strength, is consuming D3 to achieve target levels of its metabolite offering the same benefit as cholesterol transformation into Pre-D3?

  2. As adipose sequestration of high dose oral Hormone D is assumed, is there risk of toxicity in rapid weight loss?

  3. If levels are normal, but associated conditions arise, does a clinician still prescribe this medication & how much would be therapeutic?
  4. Are Hormone D levels merely a surrogate marker of healthy lifestyle? Are we chasing the white rabbit?
  5. Do high levels of this circulating hormone decrease receptor sensitivity, as we see with Insulin receptors & Insulin resistance?
  6. Estrogen has regulating effects on Hormone D synthesis, and Hormone D affects Testosterone, sometimes. How does supplementation affect these hormones?


  1. Gropper, S.S., Smith, J.L., Groff, J.L. (2005). Advanced Nutrition and Human Metabolism 4th Ed. Toronto:Wadsworth
  2. Wolf, G (2004). The Discovery of Vitamin D: The Contribution of Adolf Windaus.The Journal of Nutrition 134:1299-1302.
  3. Tsiaras, W.G, Weinstock, M.A. (2011). Factors influencing Vit D status. Acta Derm Venerol. Vol 91, Issue 2. p 115-124.
  4. Holick, M.F (2010). Vit D: Physiology, Molecular Biology & Clinical Applications. Humana Press: New York, NY, USA. p 42.
  5. Cooke, N.E., Haddad, J.G. (1989). Vitamin-D binding-protein (Gc-globulin).Endocrine Reviews 10:294-307
  6. Gomme, PT, Bertolini, J (2004). Therapeutic potential of vitamin D-binding protein. Trends in Biotechnology 22:340-345
  7. Sitrin, M.D., Pollack, K.L. Bolt, M.J.G. & Rosenberg, IH (1982). Comparison of vitamin-D and 25-hydroxyvitamin-D absorption in the rat. American Journal of Physiology 242:G326-G332
  8. Blomhoff,  R. Helgerud, P., Dueland, S., Berg, T., Pedersen, J.I., Norum, K.R. & Drevon, C.A. (1984). Lymphatic absorption and transport of retinol and vitamin-D-3 from rat intestine – evidence for different pathways. Biochimica Et Biophysica Acta 772:109-116 
  9. Holick, M.F. (2007). Vitamin D deficiency. New England Journal of Medicine 357:266-281
  10. Jones, G (2008) Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr 2008;88(suppl):582S–6S.
  11. Haddad, J.G., Matsuoka, L.Y., Hollis, B.W., Hu, Y.Z., Wortsman J. (1993). Human plasma transport of vitamin-D after its endogenous synthesis. Journal of Clinical Investigation 91:2552-2555
  12. Heaney, R.P., Armas, L.A.G., Shary, J.R., Bell, N.H., Binkley, N., Hollis, B.W. (2008). 25-Hydroxylation of vitamin D3: relation to circulating vitamin D3 under various input conditions. Am J Clin Nutr  87:1738–42.
  13. Quraishi, S.A. & Camargo Jr., C.A. (2012). Vitamin D and Major Chronic Illness.Journal of Restorative Medicine 1: 9-23.
  14. Hansen, K.E. (2011). High-dose Vitamin D: Helpful or Harmful? Curr Rheumatol Rep. June; 13(3):257-264.
  15. Bolland, M.J., Grey, A., Gamble, G.D., Reid, I.R. (2014). The effect of vitamin D supplementation on skeletal, vascular or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol. 1-14.
  16. Heaney, R.P., French, C.B., Nguyen, S., Ferreira, M., Baggerly, L.L., Brunel, L., Veugelers, P. (2013). A Novel Approach Localizes the Association of Vitamin D Status With Insulin Resistance to One Region of the 25-Hydroxyvitamin D Continuum. Advances in Nutrition. 4: 303-310.
  17. Niravath, P. (2013). Aromatase inhibitor-induced arthralgia: a review. Annals of Oncology 00:1-7.
  18. Pilz, S. Frisch, S., Koertke, H., Dreier, J. Obermayer-Pietsch, B., Wehr, E., Zittermann, A. (2011). Effect of vitamin D supplementation on testosterone levels in men. Horm Metab Res. Mar;43(3):223-5.
  19. Jorde, R, Grimnes, G., Hutchinson, M.S., Kjaerkgaard, M., Kamycheva, E., Svartberg, J. (2013) Supplementation with vitamin D does not increase serum testosterone in healthy males. Horm Metab ResSep;45(9):675-81.