Posts by Dr. Alan Jacobs, Neuroendocrinologist – neuroendocrinology.org
Doctor’s online blog source link: blog.alanjacobsmd.com/alan-jacobs-mds-blog/
A Neuroendocrine Approach To Finasteride Side Effects In Men, by Dr. Alan Jacobs (Neuro-endocrinologist)
"I have recently seen an increasing number of men who have developed significant degrees of clinical hypogonadism - low sex drive, erectile dysfunction, reduced sexual sensations and listlessness, fatigue and/or “brain fog” - while either taking finasteride or after stopping the medication, even long after stopping it.
Finasteride is a medication approved by the FDA to treat benign prostate enlargement and testosterone-related hair loss. It does so by blocking the function of an enzyme called 5-alpha reductase. This enzyme normally converts testosterone to dihydrotestosterone (DHT), which is a more potent hormone that acts at the prostate and the hair follicles. The occurrence of these symptoms in the setting of being on, or even after stopping, the medicine presents a compelling neuroendocrine problem. And it is reasonable to assume that not all men suffer from the exact same cause.
The investigation of this problem begins with measuring blood levels of the testicular hormone testosterone, DHT and luteinizing hormone (LH) and follicle stimulating hormone (FSH), which are the pituitary gland’s hormones that stimulate the testicles to make testosterone, and also estradiol, a “female” hormone that is present in men, but in much smaller amounts than in women. Small elevations in estradiol in men can have noticeable anti-testosterone effects.
If testosterone is low and LH and FSH are high, then the problem is testicular. If testosterone is low and LH and FSH are low or even normal, then the problem is “upstairs” either in the pituitary gland or in higher brain centers that control hormones. Depending on the outcome of this evaluation, treatment first and foremost involves giving enough testosterone to bring high normal levels (by gels or intramuscular shots), while blocking the conversion of some of the testosterone to estrogen, which happens naturally in fat tissue. There is a pill for this.
If high normal levels of testosterone, combined with low estrogen levels, does not relieve the hypogonadal symptoms, then the possibility that the man has some resistance to testosterone must be considered. This would be akin to the insulin resistance seen in diabetes and would be treated in a different manner. An MRI of the pituitary gland would be indicated if LH and FSH are low or normal, at the same time that testosterone is low, to exclude the possibility of a benign tumor impairing the pituitary’s ability to respond to the low testosterone.
Finally, other brain hormones can be effected by finasteride. These are called neurosteroids and their decline can bring anxiety and depression. These neurosteroids cannot yet be measured commercially with blood tests, but the “brain fog” some men experience on finasteride may result from disturbances in attention caused by anxiety or mood changes.
Finasteride certainly helps men fight hair loss and prostate enlargement. However, a considerable number of men have intolerable and sometimes persistent side effects from the medicine. A systematic neuroendocrine approach to this problem should shed light on the cause in a majority of cases and bring relief."
Here are the 2 latest posts from Dr. Jacobs on our condition. Clicking each link will take you directly to the page which is open to comments.
June 1, 2010
The Plot Thickens, Along With The Hair, When You Mess With Dihydrotestosterone
As I involve myself in the biology underlying the finasteride and post-finasteride-associated hypogonadal syndrome and parallel “brain fog” syndrome many men experience, I have focused on the metabolism of dihydrotestosterone (DHT), the hormone that finasteride inhibits by virtue of its blockage of the 5-alpha reductase enzyme that normally converts testosterone to DHT (along with several other reactions it normally does that form potent neuroactive anti-anxiety and seizure preventing hormones in the brain).
Moreover, I have written here about the role of estrogen in the brains of women (e.g. cognition, neuroprotection) and the fact that we men need estrogen in our brains also. We get it by converting testosterone to estrogen in brain cells by a different enzyme called aromatase. One might think these two pathways for testosterone conversion, one to DHT and one to estrogen, are separate and distinct. Interestingly, several brain areas important for controlling male sexual behavior use estrogen derived from testosterone.
When a man takes finasteride to block DHT and save his hair, he is likely unaware of the complexity of this hormone’s actions involving sexual behavior, stress responses, cognition and more. However, a study I recently read, Handa, RJ et al. Hormones and Behavior 53 (2008) 741-752, describes an alternative pathway for androgen regulation of brain function by estrogen receptors triggered by metabolites of DHT. [b]In other words DHT, 10 times more potent than testosterone, can itself be converted to compounds that bind estrogen receptors /b but are not estrogen.
One of these, called 3-alpha Diol, is also a neuroactive steroid that enhances the inhibitory compound GABA in the brain (like benzodiazepines and barbituates). Another, called 3-beta Diol, can act through estrogen receptors to decrease anxiety and regulate the cortisol system’s response to stress.
Without going into too much detail here, the important point is that DHT is involved in a number of metabolic pathways in the brain that create androgen-related and estrogen-related compounds that have effects on all these areas of behavior, some as promoters and others as inhibitors, some at androgen sites and others at estrogen sites, and, in at least a subset of men, interfering with this complex web of reactions by blocking DHT, may bring a lot of unwanted extra effects along with the preservation of hair.
June 21, 2010
A Proposed Mechanism For Prolonged Sexual Side Effects From Finasteride
Several young men seen for hypogonadism (low libido, erectile dysfunction, low energy, etc) after using finasteride have been found to have low-normal levels of bio-available testosterone and LH. This leads to the question of whether partial androgen resistance is at play. It has been shown that androgen insensitivity can occur even without mutations in the genes coding for the androgen receptor1. How then to connect finasteride use to the development of partial androgen resistance, especially outlasting the use of the drug?
In recent years many scientists have looked at the androgen receptor gene with an eye towards a variable length of its structure in one particular region called exon-1. In this region the number of CAG repeats, which code for glutamine (an amino acid-building block for the protein that becomes part of the receptor), vary between approximately 10-25 in different individuals and this variability has been linked to variable effectiveness or potency of androgens (testosterone(T) and dihydrotestosterone (DHT)) in these individuals. In other words, the number of these CAG repeats in the gene for the androgen receptor will effect the functionality of androgens in a man in various tissues in his body and even in his psychological traits2. This variability can cause hypogonadism in men with normal levels of testosterone, which is what androgen resistance is.
Many recent studies have looked at the CAG-repeat length of the androgen receptor in the setting of various clinical settings and found a causal relationship: in mediating the expression of testosterone deficiency on depressive symptoms, on personality traits (neuroticism, extraversion), amygdala reactivity to threat-related facial expression, body composition (muscle and fat) and circulating levels of sex hormones in young and aging men, on memory function in women, and even to solitary sexual desire in male-to-female transexuals. One study in 20053 linked the effectiveness of finasteride on men with baldness with the number of these CAG triplet repeats; the smaller the repeat number, the higher the improvement with finasteride.
I am wondering whether the propensity of finasteride to cause lasting partial androgen resistance in a subset of men relates to the number of CAG repeats in exon 1 of their androgen receptor genes, perhaps those with the greatest number of repeats are at highest risk.
I cannot even guess how finasteride would do this after the drug is discontinued, but it is certainly a testable hypothesis. Take 2 groups of men, one group without any post-finasteride hyposexuality and one group with, and measure the androgen receptor gene CAG repeat length in both groups and compare.
If it is the case, then men could be assessed, by a blood test prior to using finasteride, as to the risk of developing prolonged hypogonadism from the drug.
Clin Endocrinol (Oxf). 1996 Dec;45(6):733-9.
Int J Androl. 2003 Apr;26(2):76-83.
J Investig Dermatol Symp Proc. 2005 Dec;10(3):293-4.
Oct. 14, 2010
Another Piece of the Post-Finasteride Hypogonadism Puzzle?
The persistence of male sexual side effects (hypogonadism) after discontinuation of finasteride is a serious problem for a significant subset of men who use the drug.
I had previously written about whether the propensity of finasteride to cause lasting hypogonadism could be due to the development of partial androgen resistance and whether this relates to the number of CAG repeats in exon 1 of their androgen receptor genes.
Recently, a patient of mine brought to my attention a research paper from Csoka, et al.(J Sex Med 2008;5:227-233) titled “Persistent Sexual Dysfunction after Discontinuation of Selective Serotonin Reuptake Inhibitors”. They added 3 well-characterized case reports to the half dozen or so that were already in the literature and cited studies probing underlying mechanisms for the problem. Their fourth proposed mechanism relates to a growing field that has caught my attention in a big way, the field of epigenetics. They note that antidepressants can cause complex changes in the expression of genes. They cite animal research that has linked SSRI treatment during youth to permanantly decreased sexual behavior that persits into adulthood and that has explored underlying mechanisms for this including brain epigenetic changes at the molecular level.
Epigenetics is a field that concerns the complex web of proteins that surround our DNA. These proteins include histones, which help package and unpackage our genes to either turn on or turn off their function. “Acetylation” and “methylation” are chemical reactions that alter the histone’s function, which in turn alters the expression of our genes. Within this emerging field may lie a new mechanism by which a drug can cause persistent changes in gene expression that can influence sexual behavior.
This brings up the idea that there is a common epigenetic mechanism that may apply generally to medications that cause persistent sexual dysfunction. It may be the case with finasteride that a common epigenetic effect interacts with a less common variant in the androgen receptor gene CAG repeat profile to cause its syndrome of crippling persistent post-finasteride hypogonadism.
Human research in this area has yet to be done, but holds promise for new therapies to treat this troublesome side effect of finasteride and other widely used medications.