Post by Max on Jun 12, 2005 4:18:10 GMT -5
General overview of section 1 - (Ro)accutane and the nuclear hormone receptors
(Ro)accutane is a form of the fat soluble vitamin A that is termed a vitamin, but is classified as a steroid, and is administered to human acne-subjects in a 40-100 times overdose*, and this during several months. Metabolites of (Ro)accutane, massive doses of retinoids, that are more active forms of vitamin A, affect hormonal receptors. The retinoid metabolites of (Ro)accutane are found to affect retinoid receptors, by the high binding-affinity for vitamin A isoforms, but also a large number of other hormonal and non-hormonal receptors are found to be affected [1]. These affected hormonal nuclear receptors and other non-hormonal affected receptors are widely expressed in different cell types all over the body, in nearly every single organ, including in several parts of the human brain [10]. This is likely the reason why retinoids (Roaccutane) are used for severe diseases such as prostate cancer, leukaemia [9], glioblastoma [8] (a form of brain cancer) and other areas.
Today (as of July 2005), (Ro)accutane exposure, often in very young adolescent human subjects, is part of current dermatological practise. The skin is one of many organs that have cells that express retinoid and other nuclear hormone receptors [7]. The effects are many and one effect is that the metabolism or the cell division and proliferation is significantly reduced by significant hormonal suppression (simplified, the rate by which cells use energy is reduced). (Ro)accutane is also known to induce apoptosis, or programmed cell death [9]. This occurs in several parts of the body. In one part of the brain (the orbitofrontal cortex) the metabolism is found to be reduced by a mean of more than 20% in human subjects after four months of (Ro)accutane exposure [5].
Several deficiencies occur after exposure. Some which are measured in human subjects exposed to (Ro)accutane, including thyroid deficiency [2], androgen deficiency [3] , vitamin D deficiency [4] and vitamin A deficiency. The fat metabolism is altered. In rats exposed to isotretinoin the insulin sensitivity in peripheral tissue was found to be significantly decreased [11]. Insulin production and release are with highest certainity significantly affected, due to the structure of the insulin receptor and the retinoid interaction with pancreatic beta cells. Even the growth hormone axis is linked to activity of the nuclear receptors and vitamin A, because the retinoid receptors are found to be expressed in somatropes, the cell type that produces growth hormone [6]. The hormonal effects are wide, and even more effects that are difficult to measure, or haven´t been clinically measured in public studies are suggested. Almost all hormones have receptors in cells in the brain, where they insert actions that are not fully discovered. please see section 2. It is not speculative to say, that these receptors are not designed for a 40 to 100 times overdose of any hormone, as the doses of (Ro)accutane exert.
The retinoid receptors (RXRs, RARs), the thyroid receptors (TRs), the androgen receptors (AR), and the fat metabolism regulating PPAR receptors belong to the large superfamily of nuclear hormone receptors (NHRs), found in the nucleus of the cell, that regulate gene transcription [1]. It is not fully known what happens with these receptors, after a four month exposure of massive doses of (Ro)accutane.
(Ro)accutane induced hypothyroidism
In human acne-subjects exposed to (Ro)accutane, levels of thyroxine and triiodothyronine were significantly lower after exposure (p less than 0.05), indicating a (Ro)accutane induced clinical thyroid deficiency (hypothyroidism) [2].
(Ro)accutane is strongly antiandrogen
Roaccutane is strongly antiandrogen. A 50% suppression of androgen conversion rates have been found in related doses to what is seen in acne-subjects. The 5-alpha reductase is genetic and dependant on androgen receptor polymorphism. Androgen receptors (AR) as well as thyroid receptors (TR) belong to the superfamily of nuclear hormone receptors where also the retinoid receptors belong. The androgen receptor (AR) is a ligand-activated transcription factor that recognises and binds to specific DNA response elements upon activation by the steroids testosterone or dihydrotestosterone [3] .
Clinical observations of 1,25-dihydroxyvitamin D in human subjects exposed to (Ro)accutane
A significant fall in the level of 1,25-dihydroxyvitamin D, and a significant increase in the molar ratio of 24, 25-dihydroxyvitamin D to 25-hydroxyvitamin D was found in human subjects after exposure to (Ro)accutane, indicating a (Ro)accutane induced significant 1,25-dihydroxyvitamin D deficiency [4].
(Ro)accutane induced decreased insulin sensitivity
In all exposed rats, in 15 days, isotretinoin increased glycerol concentrations and decreased the insulin sensitivity of peripheral tissues [11].
(Ro)accutane and decreased cellular hormonal uptake
Also the hormonal uptake is suggested to be significantly inhibited, due to a significant downregulation of the megalin receptor. Androgens and estrogens are transported bound to the sex hormone binding globulin (SHBG). SHBG is believed to keep sex steroids inactive and to control the amount of free hormones that enter cells by passive diffusion. Contrary to the free hormone hypothesis, it is reaffirmed that megalin, an endocytic receptor in reproductive and other tissues, acts as a pathway for cellular uptake of biologically active androgens and estrogens bound to SHBG [12]. In mice, megalin has also shown to have an important function in the uptake of retinol [13], vitamin D [14] as well as other hormones.
*Official recommended US and European dose interval of Roaccutane by manufacturer Hoffman la Roche compared to the daily recommended intake of 800 mikrograms/day of vitamin A by the European Food and Nutrition Labeling Division
(Ro)accutane is a form of the fat soluble vitamin A that is termed a vitamin, but is classified as a steroid, and is administered to human acne-subjects in a 40-100 times overdose*, and this during several months. Metabolites of (Ro)accutane, massive doses of retinoids, that are more active forms of vitamin A, affect hormonal receptors. The retinoid metabolites of (Ro)accutane are found to affect retinoid receptors, by the high binding-affinity for vitamin A isoforms, but also a large number of other hormonal and non-hormonal receptors are found to be affected [1]. These affected hormonal nuclear receptors and other non-hormonal affected receptors are widely expressed in different cell types all over the body, in nearly every single organ, including in several parts of the human brain [10]. This is likely the reason why retinoids (Roaccutane) are used for severe diseases such as prostate cancer, leukaemia [9], glioblastoma [8] (a form of brain cancer) and other areas.
Today (as of July 2005), (Ro)accutane exposure, often in very young adolescent human subjects, is part of current dermatological practise. The skin is one of many organs that have cells that express retinoid and other nuclear hormone receptors [7]. The effects are many and one effect is that the metabolism or the cell division and proliferation is significantly reduced by significant hormonal suppression (simplified, the rate by which cells use energy is reduced). (Ro)accutane is also known to induce apoptosis, or programmed cell death [9]. This occurs in several parts of the body. In one part of the brain (the orbitofrontal cortex) the metabolism is found to be reduced by a mean of more than 20% in human subjects after four months of (Ro)accutane exposure [5].
Several deficiencies occur after exposure. Some which are measured in human subjects exposed to (Ro)accutane, including thyroid deficiency [2], androgen deficiency [3] , vitamin D deficiency [4] and vitamin A deficiency. The fat metabolism is altered. In rats exposed to isotretinoin the insulin sensitivity in peripheral tissue was found to be significantly decreased [11]. Insulin production and release are with highest certainity significantly affected, due to the structure of the insulin receptor and the retinoid interaction with pancreatic beta cells. Even the growth hormone axis is linked to activity of the nuclear receptors and vitamin A, because the retinoid receptors are found to be expressed in somatropes, the cell type that produces growth hormone [6]. The hormonal effects are wide, and even more effects that are difficult to measure, or haven´t been clinically measured in public studies are suggested. Almost all hormones have receptors in cells in the brain, where they insert actions that are not fully discovered. please see section 2. It is not speculative to say, that these receptors are not designed for a 40 to 100 times overdose of any hormone, as the doses of (Ro)accutane exert.
The retinoid receptors (RXRs, RARs), the thyroid receptors (TRs), the androgen receptors (AR), and the fat metabolism regulating PPAR receptors belong to the large superfamily of nuclear hormone receptors (NHRs), found in the nucleus of the cell, that regulate gene transcription [1]. It is not fully known what happens with these receptors, after a four month exposure of massive doses of (Ro)accutane.
(Ro)accutane induced hypothyroidism
In human acne-subjects exposed to (Ro)accutane, levels of thyroxine and triiodothyronine were significantly lower after exposure (p less than 0.05), indicating a (Ro)accutane induced clinical thyroid deficiency (hypothyroidism) [2].
(Ro)accutane is strongly antiandrogen
Roaccutane is strongly antiandrogen. A 50% suppression of androgen conversion rates have been found in related doses to what is seen in acne-subjects. The 5-alpha reductase is genetic and dependant on androgen receptor polymorphism. Androgen receptors (AR) as well as thyroid receptors (TR) belong to the superfamily of nuclear hormone receptors where also the retinoid receptors belong. The androgen receptor (AR) is a ligand-activated transcription factor that recognises and binds to specific DNA response elements upon activation by the steroids testosterone or dihydrotestosterone [3] .
Clinical observations of 1,25-dihydroxyvitamin D in human subjects exposed to (Ro)accutane
A significant fall in the level of 1,25-dihydroxyvitamin D, and a significant increase in the molar ratio of 24, 25-dihydroxyvitamin D to 25-hydroxyvitamin D was found in human subjects after exposure to (Ro)accutane, indicating a (Ro)accutane induced significant 1,25-dihydroxyvitamin D deficiency [4].
(Ro)accutane induced decreased insulin sensitivity
In all exposed rats, in 15 days, isotretinoin increased glycerol concentrations and decreased the insulin sensitivity of peripheral tissues [11].
(Ro)accutane and decreased cellular hormonal uptake
Also the hormonal uptake is suggested to be significantly inhibited, due to a significant downregulation of the megalin receptor. Androgens and estrogens are transported bound to the sex hormone binding globulin (SHBG). SHBG is believed to keep sex steroids inactive and to control the amount of free hormones that enter cells by passive diffusion. Contrary to the free hormone hypothesis, it is reaffirmed that megalin, an endocytic receptor in reproductive and other tissues, acts as a pathway for cellular uptake of biologically active androgens and estrogens bound to SHBG [12]. In mice, megalin has also shown to have an important function in the uptake of retinol [13], vitamin D [14] as well as other hormones.
*Official recommended US and European dose interval of Roaccutane by manufacturer Hoffman la Roche compared to the daily recommended intake of 800 mikrograms/day of vitamin A by the European Food and Nutrition Labeling Division
