**2.16 Post-finasteride syndrome**

The 5α-reductase inhibitor, finasteride, whose mechanism of action can be seen in **Figure 11**, is approved for treatment of benign prostate hyperplasia and male pattern baldness (androgenic alopecia). It also has off-label use among men using AAS to decrease side effects of AAS or block detection of AAS with drug tests. Effects of finasteride treatment to persistently reduce levels of DHT and 3α-diol glucoronidate have been reported among older men assessed over a years (~75 reduction from baseline; [43]. Benefits of finasteride for benign prostate hyperplasia and alopecia generally occur after chronic administration (6+ months) and subside when the treatment is discontinued [44, 45]. However, a more recent report suggests that there are individual differences in response to finasteride for alopecia. In this study, men were treated with finasteride and hair growth assessed over 10 years. Men that had the greatest increase in hair growth were those who had started treatment over 30 years of age, suggesting those that had experienced longer decline in hair growth were most responsive to the treatment. Additionally, subjects that had the greatest amount of hair growth in the first year were those same subjects who had the greatest overall hair growth over the period of the study [46]. Together, these

#### **Figure 11.**

*Prostate weight (top) and the latency to intromit in standard mating paradigm (bottom) among gonadectomized (GDX) or gonadally-intact male rats implanted with vehicle, testosterone, and/or finasteride. \* indicates main effect of gonadal condition; † indicates main effect of T condition; ‡ indicates main effect of inhibitor condition,* p *< 0.05.*

results suggest that there are individual differences in response to manipulation of 5α-reductase by finasteride. Additionally, there is evidence of individual differences in response to finasteride when considering side effects of this treatment.

The known side effects of finasteride include sexual dysfunction (e.g. loss of libido, impotence, ejaculatory or erectile dysfunction), gynecomastia, changes in cognition, and affect (including depression, which was added to the product package insert by Merck in 2010). Of particular interest is that there are side effects after finasteride is discontinued. For example, there are reports of persistent sexual dysfunction following discontinuation of finasteride [4, 46–48]. Additionally, former users of finasteride report sexual dysfunction and have high scores on the Beck Depression Inventory more than 3 months after cessation of finasteride use [2, 3]. In this study, 75% of men (61 total in the study) showing persistent sexual dysfunction following finasteride discontinuation had symptoms of depression (assessed by Beck Depression Inventory) over 3 months later. It is assumed in these individuals that endogenous androgen levels have normalized, so the question remains regarding potential mechanisms of these long-term changes in behavioral responses. A recent publication has shown that there seems to be a reduced capacity for neuroactive steroid production (as measured in cerebrospinal fluid or plasma) of individuals with side effects following discontinuation of finasteride for alopecia [49]. Studies in patients at risk for prostate cancer prescribed finasteride demonstrate increased testosterone and decreased DHT and 3α-diol glucuronide (mainly produced in the liver) in circulation [43], in addition to differences in cholesterol profile [49]. Whether levels coincide with symptoms is not understood. We have collected pilot data in support of this idea in male rats. In this study, male rats were GDX or gonadally-intact and were administered T or vehicle chronically in conjunction with finasteride or vehicle. Rats that were GDX, compared to intact rats, had lower circulating T and DHT levels, smaller prostates and longer latencies to initiate sexual contacts with a female (as to be expected). T-replacement increased plasma T and prostate mass. Similar to GDX, finasteride decreased prostate weight and inhibited sexual behavior (**Figure 11**). A preliminary finding in this study was that the finasteride treatment had variable effects to reduce the 5α-reduced metabolite, DHT, and that the levels determined do not seem to coincide with the behavioral patterns observed. As such, the present proposal is informed by the clinical literature and preliminary results in our laboratory using an animal model. Thus, of clinical relevance is consideration of long-term effects of androgen manipulations that extend beyond the treatment period. We propose, such as with post-finasteride syndrome, that there may be long-term consequences of changing androgen milieu that may be independent of specific levels of androgens at a particular time.

One factor that seems to be linking the individual differences in responses to androgens is related to different current and/or prior exposure to androgens, rather than linear effects of androgen levels for the response; additionally, effects of androgens may be via novel targets, ERβ, BDNF or GABAA activity. Studies will be challenging the current notion in field of behavioral neuroendocrinology that behavioral effects are not just due to the levels at the time the behaviors are assessed, but that there can be persistent effects beyond this. Testing this hypothesis is also a challenge to pharmacology in that effects/side effects should subside when the drug is discontinued. Proposed work is a challenge to the insular nature of science in that assessments of androgens will not only be in the brain/behavior, but also an investigation of brain effects in context of body (e.g. prostate growth/ sex behavio4). Overall, to address this question about long-term consequences of changing androgen milieu that may be independent of specific levels of androgen concentrations at a particular time and novel cellular targets for these effects, is a transformative approach to the problem that must be taken.

#### *Androgens' Effects across the Lifespan in Men and Animal Models DOI: http://dx.doi.org/10.5772/intechopen.96707*

Recently, the chemist who began making Viagra has appeared in daytime TV shows such as Dr. Oz and Dr. Phil. He has made a great deal of money for himself and his company, so much so that he feels guilty because Viagra is based on L-Arginine, which increases blood flow to all cells of the body. This was effective for ED and could be used by most people except those with risk for hypertension, heart attack, and stroke, and is readily available at low to no cost in pharmacies groceries stories. The investigator knew this, he only needed to figure out how to more specifically increase the blood flow and also had to increase not just consummatory (bigger and longer erections) aspects of behavior, but motivational (increase sex drive, sexual confidence, energy) which L-argnine itself did not do. Through my extensive pharmacological training and knowledge of naturopathic medicine, I suggest the use of Boron rather than L-Arginine so that blood flow would be more directed to the penis rather than the whole body, preventing potential side effects of heart attack, stroke, etc. Orchic could be added because it has a beneficial effect on mood patterns to reduce stress and promote relaxation. Saw palmetto is well known Asia to enhance energy, strength and stamina. Nettle extract is a known aphrodisiac that can also help boost testosterone levels. Biopterin is used to more rapidly enter target sites and boost energy, stamina, and sexual motivation. My colleague gave up most of the formula that increases testosterone and nitric oxide production in the penis and results in improved libido, sexual motivation, sexual confidence, and sexual performance. Within days there were multiple substances on the market, most of which were a supplement similar to this. It is unclear what the long-term consequences are going to be of this supplement, however it may well be a solution to using finasteride for hair growth and it may help those with post finasteride syndrome as part of their recovery on sexual side effects and ahedonia. Like all good cooks, who occasionally have memory lapses, I did not include a key naturopathic ingredient in our original formula. We do however hope to have our product patented out and on the market soon, aimed at the target audiences indicated above and hitting targets that are not just based upon ED or consummatory aspects of finasteride syndrome but also will have beneficial aspects of drive and motivation (regulated by dopamine) and impulse control regulated by the inputs on the A8, A9, A10 dopamine cell bodies (GABA, GLUTAMATE), and other drive desire aspects to socialize (oxytoxin) [50].
