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Thyroid hormone, mitochondria, photoaging and April 7, 2017


DII small banner By Warren R. Heymann, MD
Sept. 24, 2016


On April 7, 1997 I filed a patent entitled “Method for the treatment of dry skin,” utilizing topical thyroid hormone. The publication date of the patent US5951989 was September 14, 1999. The expiration date is April 7, 2017.

Some of you may remember the wonderful Demis textbook of Dermatology (with all the work involved pulling out the old chapters every year, and replacing them with updates). When I was writing a chapter devoted to the cutaneous manifestations of thyroid disease, I thought about using topical thyroid hormone for xerosis; after all, it is one of the classical features of hypothyroidism. The question was, would it work in euthryoid patients with dry skin? Certainly that must have been studied before — to my surprise, it was not. I approached Jonah Shaknai of Medicis, who graciously introduced me to their research pharmacologist, Gene Gans. I may have had the theory, but Gene was really responsible for developing the formulation of topical T4. He and Jonah insisted that the patent be in my name – realistically, it would not have been submitted without their efforts.
 
Our formulation was moderately successful in treating xerosis. The problem is that so are many other products, ranging from ammonium lactate, urea, and multiple over-the-counter moisturizers that work reasonably well, that the market for our formulation is limited. My real excitement, however, is not for xerosis, per se, but other possibilities. In 2001, I wrote: “It is also intriguing to speculate on how topical thyroid hormone would affect, and possibly benefit, other dermatologic disorders including disorders of keratinization such as Darier-White disease, the ichthyoses (i.e. ichthyosis vulgaris, X-linked ichthyosis, lamellar ichthyosis, epidermolytic hyperkeratosis, etc.) and photoaging.” (1)

The following abstract is from Vidali, et al (2). You can get sense of the multiplicity of effects that thyroid hormone has on epidermal metabolism. I added the underlining to the vital phrase.

Since it is unknown whether thyroid hormones (THs) regulate mitochondrial function in human epidermis, we treated organ-cultured human skin, or isolated cultured human epidermal keratinocytes, with triiodothyronine (100 pmol/L) or thyroxine (100 nmol/L). Both THs significantly increased protein expression of the mitochondrially encoded cytochrome C oxidase I (MTCO1), complex I activity, and the number of perinuclear mitochondria. Triiodothyronine also increased mitochondrial transcription factor A (TFAM) protein expression, and thyroxine stimulated complex II/IV activity. Increased mitochondrial function can correlate with increased reactive oxygen species production, DNA damage, and accelerated tissue aging. However, THs neither raised reactive oxygen species production or matrix metalloproteinase-1, -2 and -9 activity nor decreased sirtuin1(Sirt1) immunoreactivity. Instead, triiodothyronine increased sirtuin-1, fibrillin-1, proliferator-activate receptor-gamma 1-alpha (PGC1a, collagen I and III transcription, and thyroxine decreased cyclin-dependent kinase inhibitor 2A (p16ink4) expression in organ-cultured human skin. Moreover, TH treatment increased intracutaneous fibrillin-rich microfibril and collagen III deposition and decreased mammalian target of rapamycin (mTORC1/2) expression ex vivo. This identifies THs as potent endocrine stimulators of mitochondrial function in human epidermis, which down-regulates rather than enhance the expression of skin aging-related biomarkers ex vivo. Therefore, topically applied THs deserve further exploration as candidate agents for treating skin conditions characterized by reduced mitochondrial function.

I met with many pharmaceutical executives explaining my enthusiasm for the potential uses of topical thyroid hormone, especially for the lucrative market of photoaged skin. Understandably, they would be intrigued by the theory but wanted to see data, which I could not provide. I predict that whoever invests in unleashing the potential powers of topical thyroid hormone will be richly rewarded. When I received the patent, I had the option of purchasing a coffee cup with the patent number and title embossed on it. The patent cost me thousands of dollars in attorney fees already, so why not spend another $10? I’m glad I did, as that is all that I’m likely to show for it. One day, there will be a useful topical thyroid hormone preparation keeping skin looking beautiful, young, and vibrant. The owners of that patent will be toasting from their champagne glasses. I will tip my coffee cup in their direction to congratulate them.

1. Heymann WR, et al. Xerosis in hypothyroidism: A potential role for the use of topical thyroid hormone in euthyroid patients. Med Hypotheses 2001; 57: 736-9.
2. Vidali S, et al. Thyroid hormones enhance mitochondrial function in human epidermis. J Invest Dermatol 2016; 136: 2003-12.

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