Discussion on the new drug Accutane from 1982

General Discussion
#1

This reminded me of something I mentioned a few days ago, that initial acne flare.
Whats that about?
Probably some contradictions since this was published.

F. L. Meyskens, Jr., M.D.: The response you see
with isotretinoin is almost like a hormonal response.
We frequently see responses like this in estrogentreated breast cancer, or in response to an antiestrogen
such as tamoxifen. The patients who respond the best
are frequently those who have an initial flare-up suggesting a biphasic response. I wonder whether the effect of retinoids is mediated by an androgen receptor in
the target organ, the sebaceous gland. Is it known
whether the androgen receptor in the skin of individuals
is abnormal?

P. E. Pochi, M.D.: Individuals with severe acne
and high sebum levels have a higher content of androgen receptors in their skin. Whether these are merely a
reflection of greater sebaceous gland size in skin is not
known. But I don’t believe that isotretinoin is antiandrogenic. Did your question imply that?
F. L. Meyskens, .Jr., M.D.: There are two ways to
look at it. One, does tretinoin compete on a competitive
basis with an androgen receptor? Secondly, does isotretinoin function as an antiandrogen, either through an
androgen receptor or through some other receptor,
analogous to estrogen receptor modulation by progesterone in breast cancer? I am just tossing this out as an
idea.
P. E. Pochi, M.D.: It is not very likely. Other
androgen-responsive tissues are unaffected by isotretinoin; there is no reduction of gonadotropins or of
testosterone, and, on the basis of what Dr. Gomez
presented, there does not seem to be a peripheral antiandrogenic effect at the sebaceous gland site.
F. L. Meyskens, Jr., M.D.: But you only get acne
when you are a teenager.
P. E. Poehi, M.D.: Most cases of acne do occur in
the teen years, but some persist or even begin well after
this time.
E. C. Gomez, M.D., Ph.D.: In addition to direct
inhibition of the binding of dihydrotestosterone to the
androgen receptor, the other point of possible antiandrogen action on sebaceous cells is, of course, blockage of the conversion of testosterone to dihydrotestosterone. We have looked at isotretinoin, and it had no
effect on the 5ce-reductase. Inhibition of binding to the
receptor hasn’t been evaluated. As I mentioned, although the molecules are very different, Feldman,
Voigt, and Hsia (J Biol Chem 252:3324, 1977) did
describe an estrogen-binding protein from rat preputial
gland, and tretinoin proved to be a competitive inhibitor for estrogen binding in this system. So there may be
some sort of molecular configuration that allows a retinoid to resemble an estrogen.
P. E. Poehi, M.D.: It doesn’t inhibit 5a-reductase
activity, although it could conceivably inhibit binding,
but then if it did, the pigmentation and the hair growth
of the hamster flank organ would be suppressed, and
Dr. Gomez has shown that they aren’t. The effect on
the sebaceous gland cells is quite selective.

A side note with that,

The hamster flank organ model: is it relevant to man?

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#2

The acne flare in people taking Accutane is reminiscent of the “initial shed” often described by men taking finasteride.

I vaguely remember reading something about hamsters being a poor model of 5-ar in humans because they lack a close homolog to the human 5-ar proteins or only have one isoform. Can’t remember exactly and can’t find the article now.

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#3

A couple things I kind of forgot about, thats why I like to take notes.

13-cis Retinoic Acid Induces Apoptosis and Cell Cycle Arrest …

www.sciencedirect.com › science › article › pii
](https://www.sciencedirect.com/science/article/pii/S0022202X1532635X)

Isotretinoin (13-cis retinoic acid (13-cis RA)) is the most potent inhibitor of sebum production, a key component in the pathophysiology of acne . It is the only retinoid that dramatically reduces the size and secretion of sebaceous glands (Landthaler et al., 1980; Strauss et al., 1980; Goldstein et al., 1982).

http://www.klinikum-dessau.de/fileadmin/user_upload/Hautklinik/PDF-Files/62_oret.pdf
Isotretinoin is an extremely effective drug if given systemically in severe forms
of seborrhoea and acne, being the only retinoid with potent sebostatic properties.
Its unique activity on the sebaceous gland still remains unclear since isotretinoin
barely binds to cellular retinoic-acid-binding proteins and to retinoic acid receptors

^To me thats kind of a wow, I forgot about that one.

Sebum excretion rate in subjects treated with oral all-trans-retinoic acid

The lack of effect on the SER suggests that oral tRA would probably be ineffective against acne. The fact that, of the three isomers tested, only 13-cis-RA (which does not bind to nuclear receptors) shows activity may suggest that sebosuppression is not nuclear receptor mediated.

idk to me thats kind of a big deal to know this.
Its something ive mentioned before, you could maybe start to look at isotretinoin creating a bottleneck in normal vitamin a metabolism and what might go along with it.
Examples,

13-cis-retinoic acid competitively inhibits 3 alpha-hydroxysteroid oxidation by retinol dehydrogenase RoDH-4: a mechanism for its anti-androgenic effects in sebaceous glands?

Enzyme that digests vitamin A also may regulate testosterone levels

The scientists also found evidence that androgen receptor signaling was disrupted in the mice without the Bco1 gene. AR signaling, which regulates gene expression and is critical to the prostate’s development and function, also initiates and controls the progression of prostate cancer, according to the study.

The findings suggest that the loss of Bco1 significantly affects androgen synthesis and reduces AR signaling, decreasing cellular proliferation and growth of the prostate

Insights into the role of bacteria in vitamin A biosynthesis: Future research opportunities

#4

Just to add to this.
You see how random this is?
one minor unknown gene or enzyme disrupting ar signaling.
A good example of why not to solely focus on the AR gene.

#5

I think studies are unsure about causes of prostrate cancer, more common in bald men but also with low testosterone has also been said.

So vitamin A or retinoic acid reduces AR and this study says the opposite basically, poor A conversion low testosterone.

I’m confused

#6

Here’s maybe an example,

Night blindness precipitated by isotretinoin in the setting of hypovitaminosis A

A 16-year-old male developed night blindness 2 weeks after starting isotretinoin at a dose of 20 mg per day for cystic acne. He also had cystic fibrosis, complicated by hepatic cirrhosis. Despite long-term oral vitamin A supplementation, serum vitamin A levels were found to be 0.3 mumol/L (normal range 0.9-2.5 mumol/L). Oral vitamin A replacement was instituted with resolution of his visual symptoms in 6 months. Isotretinoin therapy was successfully continued with no deterioration in liver function. Isotretinoin has been reported to cause deterioration in night vision. In vitro evidence suggests isotretinoin may interfere with the processing of endogenous vitamin A in the retina. This case highlights the need for careful monitoring of serum vitamin A status in patients with malabsorptive states on isotretinoin therapy.

Isotretinoin-Induced Night Blindness

Isotretinoin is a gold standard drug in the armamentarium of a dermatologist for the treatment of acne vulgaris. It is the only oral drug acting on all the four pathophysiologic factors of acne vulgaris: Androgen-derived overproduction of sebum (seborrhea), ductal hypercornification (closed and open comedones), changes in microbial flora and immunologic processes and inflammation.[1] Retinal (vitamin A aldehyde) is a vital component of the photo-transduction process which is essential for normal human vision. Retinal is the crucial chromophore which combines with both rod and cone opsins to form rhodopsin and activated cone opsins. Night blindness (nyctalopia) is the most common and earliest symptom of vitamin A deficiency.[2] Isotretinoin (13- cis retinoic acid) slows rhodopsin regeneration and chromophore recycling by inhibition of the retinoid isomerase and 11- cis retinol dehydrogenase enzymes that are necessary for the synthesis of 11- cis retinal. Administering isotretinoin in patients who already have low vitamin A stores may lead to rapid development of night blindness.

Our patient developed visual symptoms within 7 days of isotretinoin therapy which resolved after 1 month of vitamin A supplementation. Halpagi et al. reported similar clinical findings in a 21-year-old female student who developed night blindness after 2 weeks of isotretinoin therapy.[5] It has been hypothesized that prior hypovitaminosis A can be a predisposing factor for isotretinoin-induced nyctalopia.[6] Does administration of isotretinoin in patients having low serum vitamin A levels makes them more susceptible to visual problems is a question yet to be answered with robust evidence. We were not able to measure serum vitamin A level in our patient. It can be postulated that isotretinoin may act as an antagonist and interfere with vitamin A in the visual pathway.