Accomplished Molecular Biologist Nadine Hornig Discusses Post-Finasteride Syndrome
Nadine Hornig, PhD is Principal Investigator at the Institute for Human Genetics at University Medical Center Schleswig-Holstein and Kiel University.
Dr. Hornig conducts research in the areas of molecular biology, genetics, epigenetics, and endocrinology and was recently published in the distinguished journal Nature for her paper, "Formin-mediated nuclear actin at androgen receptors promotes transcription."
She is a member of PFS Network's scientific advisory board and lead researcher on the charity's current epigenetics study in Kiel. The following are highlights from the podcast with Dr. Nadine Hornig and PFS Network President Mitch Sabine recently uploaded to the charity’s Youtube channel.
To date, Dr. Hornig’s work has been focused on a condition called androgen insensitivity syndrome (AIS). Individuals affected by AIS are born with either under-developed male genitalia or female genitalia, although they are biological males, having an XY genotype. Most commonly, AIS is caused by mutations in the androgen receptor gene. The androgen receptor (AR) is the receptor that receives the signal from androgens, such as testosterone and dihydrotestosterone (DHT), and spurs male genital development in embryogenesis, or prenatal development.
However, a small percentage of individuals with androgen insensitivity syndrome do not have a mutated androgen receptor gene. Much of Dr. Hornig’s research has aimed at trying to understand what is driving the condition in those patients.
Through this she was able to identify an androgen receptor cofactor needed for regular male sex development, which patients with AIS but without an androgen receptor mutation, did not possess in normal amounts. A cofactor is a factor needed for a protein, like the androgen receptor, to work properly. The discovery of this cofactor allowed for diagnosis of an epigenetics-mediated form of AIS.
“Dr. Hornig: This recent publication, Nature, is basically about a cofactor of the androgen receptor that we identified that is also needed for regular male sex development.
Dr. Hornig: I’m trying to find out these cofactors. A lot of cofactors have already been described in prostate cancer, but for male sex development this has not been done in detail.
Mitch Sabine: Okay, interesting. So, when we think about the syndrome, you know one of the ways I’ve heard it described, is this syndrome, or the type of AIS which you discovered, is driven by epigenetics rather than the code mutation.
Dr. Hornig: Right… So, epigenetics is basically everything that is regulating gene transcription. Regulation of gene transcription happens at promoters and enhancers of genes, and so we had this cohort of patients where we saw an epigenetic silencing of the promoter of the androgen receptor… In these patients, there was a silencing where there should not have been, a silencing of the androgen receptor. ”
If someone has an impaired function, or silencing, of the androgen receptor, they do not go through prenatal development or puberty normally. Other known problems with the androgen receptor arise from gain of function mutations, where androgen receptor signaling can mediate prostate cancer.
“So, not enough, bad, too much, bad. It’s kind of like the ‘Goldilocks zone.’”
Dr. Hornig became interested in researching post-finasteride syndrome (PFS) after she was contacted by a member of PFS Network, who connected her previous research to the condition. She did not actually know of PFS beforehand, but the charity was able to convey to her how serious and debilitating the condition is for many patients. She was intrigued that the condition is permanent, that symptoms do not resolve, and this made her suspect epigenetic changes could be involved. Dr. Hornig’s immediate thought was that it appears an epigenetic switch is triggered by the drug, which causes the affected cells to no longer respond to androgens in a normal way.
For the current epigenetics study in Kiel, which Dr. Hornig is lead researcher on, several assays will be performed on cells from patient genital tissue (genital skin fibroblasts to be precise). Next generation sequencing will be done to analyze whole genome expression and androgen receptor expression, the results of which can be compared to previous research on the condition.
In addition, the Kiel scientists will look at methylation patterns in the androgen receptor regulatory region of the genome, and they will look at chromatin structure. Methylation is a marker for gene transcription, so that usually if there is high methylation at a promoter, there will be reduced gene transcription, and vice versa. Chromatin also affects gene expression: if chromatin is open (packed less densely), genes can be transcribed and translated. If chromatin is closed (packed more densely), genes cannot be transcribed and translated.
“Dr. Hornig: …it’s more a system where I want to understand what is happening to the androgen receptor or everything surrounding the androgen receptor.
Mitch Sabine: And then we work with Dr. Urbanucci to figure out why that someone out of, you know, a lot of people who take the drug or only a certain number of people are affected.
Dr. Hornig: Exactly. ”
The outcome patients can expect from this study will be data, and a large amount of it. It will serve as a necessary groundwork for further research on the condition.
“Dr. Hornig: Yeah so, I mean we first need to get a picture of what is happening in these cells. Right now, I don’t have many clear hypotheses yet. I first want to know, okay, is the androgen receptor working properly in these cells, is it expressed in a normal way, can it be activated in a normal way… Once I have all these results, then I can start thinking about a hypothesis, what could go, or what went, wrong after the drug.
Dr. Hornig: What might outcomes of this look like? Well, we will have a lot of data that we will have to analyze, so the primary outcomes are basically, yeah, data that we hopefully see some differences between the patients and the controls.
Mitch Sabine: Excellent. Well, I think that just about covers everything for today. Appreciate the crash course into epigenetics and the AR and everything you’re working on – really appreciate all your efforts and thanks for being involved and speaking with me.
Dr. Hornig: Welcome, and it was really nice speaking to you. I hope this study will work out as we expect to. I’m quite positive. I think we’re in a good way. ”