Vitamin D, the anabolic switch?

vitamin structure

Vitamin D has several beneficial effects on health. It’s really crucial for balance and proper organic function, participating in numerous “first line” biochemical reactions. However, it is not about these well-known functions that I will talk about in this article. Would you be surprised if I told you vitamin D has anabolic properties?

Biochemistry

From a chemical point of view, it would be more correct to consider vitamin D a pro-hormone than a vitamin.1 As a cholesterol derivative, vitamin D is synthesized from cholecalciferol which is a product of the ultraviolet (UV) action on the 7-dehydrocholesterol found in the skin.2 In 1966, it was recognized that the activation of vitamin D has to undergo two oxidative metabolic steps. The first oxidative step, which involves 25-hydroxycholecalciferol (25(OH)D3 ) occurs in the endoplasmic reticulum of hepatocytes and is catalyzed by the enzyme Vitamin D 25-hydroxylase.1,2 This biochemical pathway, however, is not regulated by serum calcium concentrations.

The most common circulating form of vitamin D is 25(OH)D3, which is found in plasma concentrations of (10-80µg/ mL). This is also our primal storage mechanism.2

In response to hypocalcaemia and secretion of PTH (parathormone), a second oxidative step is activated in the kidney mitochondria, catalyzed by the enzyme vitamin D 1-α-hydroxylase.2,3 The product of this reaction is the formation of 1,25-dihydroxycholecalciferol (1,25-calcitriol), the active form of vitamin D.

The biosynthesis of vitamin D is, in accordance with previously described, strictly controlled by serum calcium, phosphate, PTH and vitamin D (substrate regulation).

You are probable tired of all this geek biochemistry talk, so … let’s analyze vitamin D in terms of its chemical structure and function … Ready to dive into a bit of Organic Chemistry?

Chemical structure

Vitamin D3 has a IUPAC name of (3β,5Z,7E)-9,10-secocholesta-5,7,10(19)-trien-3-ol. Probably by now you thought… WHAT?! Honestly I completely understand you! The reason why chemists like IUPAC names better than common names is basically because IUPAC names say a lot about a compound structure 🙂 It is important to know the structure to understand how a compound works in your body, particularly the functional groups involved.

Vitamin D has a structure with four rings (A, B, C, and D), typically called gonane (in some literature, steran nucleus) which is common to steroid hormones and derivatives.4 The fact of having a structure similar to a steroid, does not necessarily mean that has the same affinity for the androgen receptor. A molecule, having a similar structure, can in fact be a receptor antagonist (blocks the receptor, not allowing signal transduction).2 In order to end the geek talk, in the case of vitamin D it has a similar structure (except it is a secosteroid) which has affinity for the androgen receptor, probably activating it.5

If we wanted to summarize the formation of vitamin D to simple chemistry, we would say that the 7-dehydrocholesterol, originates pro-vitamin D3 by opening the B ring at the C(9)-C(10) bond, which in turn undergoes isomerization yielding Vitamin D3 . For this reason, it is absolutely critical for the compound originating pro-vitamin D3 to be a sterol with double bonds (Δ-5,7-dien) at the B ring.2,4

nrc2196-f1

Anabolic properties

Vitamin D is essential for absorption and metabolism of calcium and phosphorus, it also promotes bone health.6 Low levels of this vitamin, something that is common to the western world are directly related to cancer and cardiovascular disease.6 Vitamin D, as expected, has the ability to bind to the vitamin D receptor (VDR). This receptor is known to regulate hundreds of genes; many of them involved in muscle hypertrophy and increased strength.7 The relationship between vitamin D and testosterone production is also well known.8 It is a strong possibility that vitamin D supplementation may elevate testosterone.9

This connection between testosterone levels and vitamin D is not only clear, as apparently a connection with the sex hormone binding globulin (SHBG) also exists.10 As it is generally recognized, approximately 98% of testosterone is not available for interacting with target cells since it is mostly inactivated by binding to serum albumin and SHBG. It is believed that optimum levels of vitamin D, may reduce the amount of SHBG, thus enabling higher free testosterone.10 This may explain the anabolic properties of vitamin D.

Since vitamin D depends mostly from exposure to solar radiation, it was showed that there is a strong relationship between the season of the year and levels of vitamin D and testosterone.10 In the summer, there are obviously higher levels of Vitamin D and testosterone, by increased exposure to solar radiation. In the winter the situation is the opposite, leading us to a situation in which our body depends much more on dietary vitamin D.10

If we want to go a bit deeper into this subject, in a press release of the year 2011, one of the leading companies in the research of sarcopenia (decrease of muscle mass) claimed that vitamin D increases the expression of the androgen receptor in myocytes (muscle cells).11 Apparently vitamin D increased the conversion of satellite cells into new muscle fibers and also raised the possibility of administering nandrolone decanoate together with vitamin D to enhance its activity.11 According to this press release, nandrolone decanoate also acts on the VDR.11

More recently, the same company reported that the administration of vitamin D in conjunction with nandrolone decanoate, improves its safety profile.12 Apparently vitamin D, prevents the proliferation of prostate cells, being this a key marker of unwanted androgenic effects.12 According to this study, vitamin D can reduce the androgenic activity of testosterone.12

To resume everything that has been said, vitamin D can:

a) Increase the activity of the androgen receptor and VDR.

b) Reduce the levels of SHBG.

c) Reduce the androgenic activity of testosterone and similar hormones.

We know that both the activity of the androgen receptor and free testosterone levels, are critical in protein synthesis and muscle hypertrophy.13

Personally, I am convinced that vitamin D is more anabolic than we suppose … Again, this is just my opinion, not a scientific fact!

Decreasing aromatization of steroids with vitamin D

Aromatization, in simple terms, is the process by which androgens (e.g. testosterone) are converted to estrogens (e.g. β-estradiol) by the action of the enzyme aromatase.

The aromatization of androgens to estrogens in the testes and extra glandular tissues of man is realized by the same enzyme complex present in the ovary and placenta, CYP19. The aromatization of androgens involves sequentially: hydroxylation, oxidation and removal of the C(19) with the aromatization of the A ring of the steroid.13

3 mole of NADPH and 3 mole of oxygen are needed to convert 1 mole of testosterone or androstenedione to estrone and estradiol, respectively.13 The oxidation in this process, involves a specific cytochrome P450 (CYP 19). Enzymes involved appear to be linked to a microsomal complex that includes the NADPH-cytochrome P450 reductase and cytochrome itself.13

From about 45 mg daily of estradiol produced in the body of a young male, only about 10 to 15% comes directly from testicular secretion, the remaining 85 to 90% are derived from peripheral aromatization of androstenedione (for estrone) and testosterone. 13 The formation of estrogens in the testes appears to be influenced by the levels of luteinizing hormone (LH) and human chorionic gonadotropin (hCG).13 Aromatization in peripheral tissues, although it does not seem to be affected by gonadotropins, increases with age.13

Vitamin D has demonstrated the ability to reduce the expression of the enzyme aromatase, primarily in adipocytes and estrogen-sensitive breast carcinoma.14 Moreover, in this type of cancers, Vitamin D decreases the action of prostaglandins in the breast tissue by suppressing cyclooxygenase-2 (COX-2 ), elevating simultaneously 15-hydroxyprostaglandin dehydrogenase (which catalyzes prostaglandin degradation.)14 Prostaglandins stimulate aromatization, so they are major players in estrogen dependent diseases.14

Although this study was done in rats,14 the effect of the inhibition of aromatase in human seems a very plausible hypothesis with vitamin D. This work also showed an increase on the effect of aromatase inhibitors (anastrozole, letrozole and exemestane), when administered with vitamin D.14

There are numerous studies on vitamin D: associated with the prevention of prostate cancer,15 Infertility16 etc… Since the world population seems to be widely deficient in this vitamin,17 why don’t you get a little more sun or at least take some vitamin D supplements (if required)?

Note: You should not take vitamin D supplements before checking your vitamin D levels. The marker you should look for is 25(OH)D3. If you have between 30-40ng/mL you’re on the healthy level.18
If you really want to know a lot about vitamin D, please refer to the literature of Professor Michael F. Holick, Ph.D. or Professor Reinhold Vieth, Ph.D. These are in my opinion the two top researchers on this vitamin.

Filipe Teixeira

Technical Manager-Body Temple Ltd.

The Tudor Bompa Institute, Portugal.

Director of Nutrition TBI-International.

The opinions contained herein reflect only the opinion of the author and not necessarily of Body Temple Ltd/Tudor Bompa Institute. Always check with your doctor or healthcare professional before embarking on any supplement, diet plan or treatment.

 

Bibliography:

1. Devlin TM. Textbook of Biochemistry with Clinical Correlations. 7 th Edition. New Jersey:John Wiley & Sons; 2011. 

2. T Lemke, et al. Foye’s Principles of Medicinal Chemistry. 6 th Edition. Philadelphia: Lippincott Williams & Wilkins; 2008. 

3. DeLuca HF, Zierold C. Mechanisms and functions of vitamin D. Nutr Rev 1998;56:S4-S10. 

4. KPC Vollhardt, NE Schore. Organic Chemistry: Structure and function. 6th edition. New York:Freeman; 2009. 

5. Proal AD, Albert PJ, Marshall TG. Dysregulation of the vitamin D nuclear receptor may contribute to the higher prevalence of some autoimmune diseases in women. Ann NY Acad Sci 2009 Sept;1173:252-9. 

6. Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 2004;80(6):1678S-88S. 

7. Ramagopalan SV, et al . A ChIP-seq defined genome-wide map of vitamin D receptor binding: Associations with disease and evolution. Genome Res 2010;20(10):1352-60. 

8. Reichel H, et al . The role of the vitamin D endocrine system in health and disease. N Eng J Med 1989;320(15):980-991. 
  
9. Pilz S, et al . Effect of vitamin D supplementation on testosterone levels in men. Horm Metab Res 2011 Mar;43(3):223-5. 

10. Wehr E, et al . Association of vitamin D status with serum androgen levels in men. Clin Endocrinol (Oxf) 2010 Aug;73(2):243-248. 

11. Vitamin D stimulates expression of androgen receptor in human skeletal muscle [Internet]. Arnhem:Organext; posted on 2011/06/4; [accessed 12 August 2012]. Available from: http://www.organext.com/

12. Addition of vitamin D Improves safety profile of nandrolone [Internet]. Houston:Organext; published on 06.25.2012; [accessed 12 August 2012]. Available from: http://www.organext.com/

13. Griffin JE, Ojeda SR. Textbook of Endocrine Physiology. 5th Edition. New York:Oxford University Press; 2004. 

14. AV Krishnan, et al. Tissue-selective regulation of aromatase expression by calcitriol: implications for breast cancer therapy. Endocrinology 2010 Jan;151(1):32-42. 

15. ES Leman, et al. Vitamin D and androgen regulation of prostatic growth. J Cell Biochem 2003 Sep;90(1):138-147. 
  
16. Lerchbaum E, Obermayer-Pletsch B. Vitamin D and fertility: a systematic review. Eur J Endocr 2012;166:165-778. 

17. Alshishtawy MM. Vitamin D Deficiency: This clandestine endemic disease is veiled no more. SQU Medical Journal 2012 May;12(2):140-152.

18. Shills M, et al. Modern Nutrition in Health and Disease. 10th Edition. Philadelphia:Lippincott Williams & Wilkins; 2010

 

 

Advertisements

2 responses to “Vitamin D, the anabolic switch?

  1. We are a group of volunteers and starting a
    new scheme in our community. Your site offered us with valuable information
    to work on. You’ve done a formidable job and our entire community will be thankful to you.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s