It is becoming increasingly clear that Isotretinoin elicits many anti-androgenic actions; but, for the purposes of this discussion I would like to centre my attention on the seemingly tentative relationship between healthy penile function and dihydrotestosterone. There are three isoforms of 5 alpha-reductase: type 1, type 2 and the newly discovered type 3.
Isotretinoin is a known 5 a-reductase type 1 inhibitor. Isotretinoin inhibits the critically important type 1 isoenzyme which predominates in the skin, brain and liver. It should also be noted that type 1 5 a-reductase transcribes from type 1 to type 2 in human skin genital fibroblasts. So when we argue that only 5 a-reductase type 2 is pertinent to penile erection, and health, we are technically being incorrect, as type 1 effectively transcribes to type 2. Please note that peripherally produced (tissue derived) hormones which are suppressed by Isotretinoin contribute to the circulatory pool in serum.
5 a-reductases also participate in: bile acid biosynthesis, and androgen metabolism and estrogen metabolism. 5 alpha-reductase type 1 inhibition in the brain affects the production of the neurosteroid allopregnanolone. Allopregnanolone inhibition is associated with depression. 5 a-reductase type 1 is crucial to the optimal function of the central nervous system. It is clear that Isotretinoin affects a plethora of hormones and systems within the body, but just the inhibition of the 5 alpha-reductases is cause for concern.
I ask all those who feel that Isotretinoin is definitely not involved in sexual dysfunction to take a close look at the studies listed below:
The most pronounced effect was observed in skin biopsies, which lost 80% of their ability to form 5 alpha-dihydrotestosterone (P < 0.001). It is concluded that 13-cis-RA therapy in men with severe nodulocystic acne did not alter gonadal or adrenal functions, but it did induce 1) a highly significant decrease in 5 alpha-dihydrotestosterone formation by skin biopsies; 2) significant decreases in serum 5 alpha-dihydrotestosterone, androsterone glucosiduronate, and 5 alpha-androstan-3 alpha, 17 beta-diol glucosiduronate; and, finally, 3) deviation of the liver androgen 5 alpha- to 5 beta-reduction pathway. The effect of 13-cis-RA treatment on severe acne is consistent with the dramatic decrease in androgen 5 alpha-reduction observed mainly in the skin.
Description of 5 -reductase deficiency in male pseudohermaphroditism caused investigators to study the influence of 5ARIs on erectile function in animal models. To begin to unravel this issue, Bradshaw and associates (1981) designed a study in which they administered the 5ARI, 17-beta-testosterone carboxylic acid and T propionate or 5 -DHT propionate, after castration of animals. The investigators observed significantly attenuated stimulatory effects of T propionate on penile erections. However, when they administered 5 -DHT propionate to castrated rats, penile erections were preserved, implying the importance of DHT in erectile function (Bradshaw et al, 1981).
The inhibitory effect of 17 beta-testosterone carboxylic acid on erection was reversed by concurrent administration of 5 alpha-dihydrotestosterone propionate, suggesting that the 5 alpha-reduced metabolite(s) of testosterone may normally contribute to the activation of penile erection in the rat.
Isotretinoin had no meaningful effects on precursor androgens, except for producing an elevation of free T in women. In contrast, isotretinoin produced depressions in the serum levels of DHT and 3 alpha-diol G in women and in 3 alpha-diol G in men. These decreases are believed to be the result, rather than the cause, of a reduction in the size of the sebaceous glands: The magnitude of the observed decreases may represent the amount of tissue-derived androgens that sebaceous glands normally contribute to the circulating pool.
Despite the central and peripheral effects of androgens on the nervous system, the local effects of androgens in the corpus cavernosum penis and their importance for erectile function is still unclear. In this study corpus cavernosum biopsies of eight adult potent patients, aged 19–63 years, undergoing penile deviation surgery The significant and age-independent high androgen and low estrogen-alpha receptor distribution found in both groups suggests a possible peripheral effect of androgens at the level of the corpus cavernosum penis in adult humans. This is supported by the observed effect of testosterone and dihydrotestosterone on cell count and endothelial cell metabolism in our cell culture system. The role of estrogens remains unclear
5-Alpha-reductase inhibitor drugs are used in benign prostatic hyperplasia, prostate cancer, and baldness. Both isoforms are also produced in the brain, where they serve to create the neurosteroid allopregnanolone (5AR type I) and convert T to DHT(5AR type II)(1
The present review describes concisely the topography and function of the three androgen-metabolizing enzymes, namely aromatase, 5α-reductase and 3α-hydroxysteroid dehydrogenase, in the central nervous system (CNS). Steroid 5α-reductase converts a number of steroids with a C3 ketone group and a C4–C5 double bond (Δ4; androgens, progestins and glucocorticoids) to their 5α-reduced metabolites. Two isoforms of 5α-reductase are found and type 1 is predominant in neural tissues. The enzyme activity of 5α-reductase is found widely in the CNS and is high in white matter regions
5alpha-reductase is a critical enzyme in the conversion of several steroids such as testosterone, progesterone, aldosterone and corticosterone in the brain. This enzyme converts testosterone to the most natural potent androgen DHT, and also it acts an important role in conversion of progesterone to dihhydroprogesterone (DHP). DHP is further converted to allopregnanolone (5alpha, 3alpha-tetrahydroprogesterone) by 3alpha-HSD [9,21]. Allopregnanolone is a modulator of gamma amino butyric acid type A receptor (GABA-A), and increases chloride conductance. This neurosteroid has been found to exert anti-convulsant, anesthetic and anxiolytic effects [22-24]. Moreover, change in the levels of allopregnanolone is found to be associated with depressive disorders. [25,26]
Edited by Modestm, 23 May 2011 - 02:42 AM.