Finasteride Drug origin, pharmacology, AR structure and androgen action

Androgens, the androgen receptor and the expanding understanding of its role in health

Androgens are well appreciated for their critical developmental role in sexual differentiation ​(Forger, 2018)​, male characteristics, the development and maintenance of male sexual organs and sexual function ​(C J Bagatell et al., 1994; Podlasek et al., 2016; A. M. Traish, 2008; Yamada et al., 2006)​. However, androgens are now known to play a “pleiotropic role…in virtually all body systems” ​(Gibson et al., 2018)​. Gibson et al. identify four key areas in which the understanding of the role of androgens has evolved and expanded in the 21st century: Testosterone’s recognition as a “Goldilocks” molecule, with too much or too little androgen signalling disrupting cellular homeostasis and proving deleterious to health, a dynamic and tissue specific regulation of intracrine androgen metabolism, an increased understanding of the role of androgens in female reproductive tissue, and the extensive role for androgen-mediated regulation in tissue beyond the reproductive system in both sexes ​(Gibson et al., 2018)​. At the tissue level, there are tightly controlled optimum levels for androgen concentrations. Owing to the crucial role of androgen intracrine biosynthesis and metabolism in the physiology of peripheral tissues in males and females, dysregulation can impair both local and systemic metabolic homeostasis ​(Carrie J. Bagatell & Bremner, 1996; Schiffer et al., 2018)​.

Nuclear receptors are ancient proteins well conserved across evolutionary time and are present across the Metazoa ​(King-Jones & Thummel, 2005)​. The effects of androgen steroids are primarily mediated through the Androgen Receptor ​(Verhoeven & Swinnen, 1999)​, a class I steroidal receptor protein which binds androgens as ligand in the cytoplasm, dissociates from chaperones and translocates to the nucleus ​(Davey & Grossmann, 2016; Ni et al., 2013; Tsai & O’Malley, 1994)​. The AR is ubiquitously expressed across most bodily tissues including the brain and nervous system, penis, testes, prostate, skeletal muscle, skin, liver, urinary bladder, gastrointestinal tract, arteries, kidneys, breast, uterus, bone, adrenal glands, and teeth ​(Dale et al., 2002; Fujimoto et al., 1994; Gannon et al., 2019; Heemers & Tindall, 2007; Khalil et al., 2018; Kimura et al., 1993; Mhaouty-Kodja, 2018; Ruizeveld de Winter et al., 1991; Schultheiss et al., 2003; Sinha-Hikim et al., 2004; Vanderschueren et al., 2014; Verhoeven & Swinnen, 1999; Wu et al., 2019; Xia et al., 2019)​. Significant evidence has demonstrated the AR is expressed across many areas of the brain in both sexes including the temporal, medial preoptic, hypothalamus, amygdala, bed nucleus of the stria terminalis, midbrain, frontal and prefrontal areas, cingulated gyrus, and limbic regions including the hippocampus, where it is critical to important neurocognitive functions including reproductive behaviour, reward behaviour, learning, memory, spatial awareness and metabolic regulation ​(Beyenburg et al., 2000; Brock et al., 2015; Lu et al., 1998; Morford et al., 2018; Shah et al., 2004; Simerly et al., 1990; Tobiansky et al., 2018)​. The role of the AR in disease cannot be overstated ​(Koryakina et al., 2014)​ owing to its role as an important hub mediating multiple cellular signals and functions ​(Lai et al., 2012)​.

The AR is coded from eight exons located in the long arm of the X-chromosome ​(J. Brand & M. Dehm, 2013; Lubahn et al., 1988)​, lacks a TATA and CCAAT box in the regulatory promotor, and is comprised of four distinct domains acting together to mediate genomic effects of androgens in target tissue. These are the N-terminal domain, the DNA binding domain, the hinge region, and the C-terminal ligand binding domain ​(Brinkmann et al., 1989; Lanciotti et al., 2019; Mangelsdorf et al., 1995; I J McEwan, 2004)​. The AR is regulated by ligand binding, interaction of functional domains (such as N/C terminal interaction), homodimerization and cofactor interactions ​(van Royen et al., 2012)​. The N-terminal domain is intrinsically disordered and exists as collections of conformers, allowing rapid impermanent structural alterations in response to the cellular environment and binding of multiple coregulators with distinct outcomes ​(Kumar & McEwan, 2012; I. McEwan & Monaghan, 2016)​. This region contains polymorphic glutamine and glycine tracts ​(Wadosky & Koochekpour, 2016)​. The ligand independent AF-1 surface in the N-terminal domain interacts with coregulators ​(Heinlein & Chang, 2002)​. More than 200 AR-interacting proteins with either coactivator or corepressor activities are known ​(Chang & McDonnell, 2005)​. The open structure of the ligand binding domain (LBD) adopts a compact structure when bound to agonists, which are then sealed within hydrophobic interior ​(Iain J. McEwan & Kumar, 2015)​. Helix 12 is repositioned to form a surface for transcription promoters ​(Hur et al., 2004)​. The LBD contains AF-2 which is pivotal to the ligand-dependent full activation of the androgen receptor ​(Narayanan et al., 2018)​ and is affected by coregulators. The AF-2 has high affinity for a highly conserved 5-residue FQNLF motif in the N-terminal segment of the N-terminal domain. The LBD binding to this region facilitates activation, and molecular chaperones compete for binding and prevent activation of the AR in a delicate balance of protein-protein interaction that is seemingly regulatory of activity, solubility, concentration and AR turnover ​(Eftekharzadeh et al., 2019)​. A nonclassical zinc finger structure in the DNA Binding Domain functions to recognise and make contact with nucleotide sequences, while a second mediates dimerization on DNA ​(Iain J. McEwan & Kumar, 2015)​. The activation of the AR and targeting of androgen response elements results in increased transcription of a host of genes, many of which control cell growth, proliferation and regulation of apoptosis ​(Heemers & Tindall, 2007)​. Liganded AR also activates coregulators distinctly from its DNA binding capability ​(Slagsvold et al., 2001)​. The human AR has AREs and autoregulates its own gene in a tissue-specific manner ​(Hunter et al., 2018)​. The AR has functional roles beyond transcription, and nonclassical AR mediated actions occur via the ERK, SRC, PI3K, MEK and AKT pathways ​(Deng et al., 2017; Vanderschueren et al., 2014)​. Recently, ubiquitously expressed specific G protein-coupled receptors known as membrane androgen receptors have been described by which androgens mediate rapid intracellular actions and diverse nonclassical processes, eliciting significant physiological and behavioural effects in animals and humans within seconds or minutes ​(Balthazart et al., 2018; Foradori et al., 2008; Geniole et al., 2019; Kalyvianaki et al., 2019; Thomas, 2019; Thomas et al., 2018)​. Testosterone association to membrane AR exerts a rapid regulatory influence over classical genomic AR signaling ​(Deng et al., 2017; Li et al., 2018)​, and appreciation of these effects are therefore more accurately characterised as nonclassical as opposed to nongenomic ​(Balthazart et al., 2018)​. The rapid nonclassical actions of the mAR ZIP9 are vulnerable to disruption by endocrine disrupting chemicals known to interfere with classical androgen signaling, and the toxicological consequences of this are currently unclear ​(Thomas & Dong, 2019)​.

The primary male steroid hormone and AR ligand testosterone is produced by the Leydig cells of the testes (Schiffer et al., 2018). Testosterone is synthesised from cholesterol (Miller, 1988) through a number of steps originating with p450 side-chain cleavage conversion to pregnenolone in the inner mitochondrial membrane (Selvaraj et al., 2018). Leydig cell production of testosterone is stimulated in response to the anterior pituitary releasing LH in response to a pulsatile release of LHRH by the hypothalamus, and testosterone regulates LHRH release via a negative feedback loop (Heemers & Tindall, 2007). Androgen signalling is amplified in target tissue through the metabolism of T to 5α-dihydrotestosterone (DHT). DHT is the most potent endogenous androgen (Pretorius et al., 2016; Rege et al., 2013), with a four-fold higher binding affinity for the androgen receptor (Gao et al., 2005) and a three-fold lower dissociation rate than that of testosterone (Wilson & French, 1976). Agonists form hydrogen bonds to the AR with high occupancy, with DHT bonding to residue Thr877 and testosterone bonding at Asn705 (Azhagiya Singam et al., 2019). DHT binding causes the AR to undergo conformational change to its DNA binding state (Kovacs et al., 1984), and increases synthesis and degradation of the AR protein (Syms et al., 1985). However, tissue-level factors regulating metabolism including local intracellular ligand concentrations influence binding in addition to relative ligand affinities, and as such DHT does not always bind preferentially compared with T (Swerdloff et al., 2017).

Circulating T is more important than serum DHT for optimizing the intracellular DHT concentrations due to the presence of a rate-limiting enzyme, 5a-reductase. Testosterone is metabolised to DHT irreversibly by the catalytic microsomal enzyme 5α-reductase type 2. 5AR2 is a hydrophobic membrane-bound protein comprised of 254-260 amino acid residues (Russell & Wilson, 1994). The 5α-reductase family of enzymes are diffusely expressed across a large number of tissues, and exert a profound effect on human health due to their regulation of steroid metabolism and metabolic functions including glucocorticoid clearance ​(Abdulmaged M. Traish et al., 2014)​. 5ar enzymes catalyze the reduction of the double bond in the A-ring at Δ4,5 position in C-19 and C-21 steroids ​(Azzouni et al., 2012; Abdulmaged M. Traish et al., 2015)​.

Development and pharmacology of Finasteride

Loss of appropriate androgen signaling is associated with diverse detrimental effects in males, as evidenced by the well appreciated side effects of androgen deprivation therapy. ADT is known to induce bone problems, metabolic dysfunction, sexual dysfunction, reduction of penile and testicular size, gynecomastia, fatigue, vasomotor flushing, memory, cognitive and psychosocial impairments ​(Nguyen et al., 2015)​. Heightened androgen action is directly implicated in pathologies including benign prostate hyperplasia, prostate cancer ​(Banerjee et al., 2018)​, bladder cancer ​(Gil et al., 2019; Liu et al., 2018)​, androgenic alopecia ​(Lai et al., 2012)​, lower urinary tract symptoms and polycystic ovary syndrome ​(Apparao et al., 2002)​. As 5alpha reductase is largely responsible for tissue DHT levels, 5alpha reductase inhibitor products can alleviate symptoms owing to reducing pathological androgen receptor activation. Significant increases in serum DHT via exogenous DHT administration have little effect on prostate DHT concentrations, prostate size, and lower urinary tract symptoms ​(Swerdloff et al., 2017)​. Considering misconceptions likely arising from the lowered serum levels following 5alpha reductase inhibitor therapy coinciding with symptomatic relief in these domains, Swerdloff et al. note this illustrates fundamentally important control mechanisms in androgen target tissues that finely regulate androgen synthesis and degradation pathways to maintain DHT homeostasis, to which circulating DHT levels are of much less importance than that of T ​(Swerdloff et al., 2017)​. Beyond these primary androgens, around 5-10% of serum androgens include dehydroepiandrosterone, androstenediol, and androstenedione, which can be produced by ACTH-regulated adrenal synthesis ​(Rainey et al., 2002)​.

The prostate is a strictly androgen dependent structure ​(Banerjee et al., 2018)​. The link between androgens and prostate growth was established in the mid-20th century ​(Nelson, 2016)​. Concurrently, androgens were understood to be both a strict requirement and driver of male pattern hair loss ​(Hamilton, 1942)​. The selective 5alpha-reductase type 2 inhibitor Finasteride is a 4-azasteroid that was developed as a treatment for benign prostate hyperplasia (BPH) and androgenic alopecia (AGA) by Merck. This programme followed Imperato-McGinley’s identification and profiling of pseudohermaphroditism in males with genetic 5aR deficiency ​(Imperato-McGinley et al., 1974, 1991)​. These (46XY) males demonstrate at birth a marked ambiguity of external genitalia and are frequently raised as girls. However, a notable change occurred at puberty during which they developed a typical male phenotype, including virilisation of ambiguous genitalia into a functional penis and male psychosexual orientation regardless of prior female designation and rearing ​(Imperato-McGinley et al., 1974; Imperato-McGinley & Zhu, 2002)​. In adulthood this cohort display little body hair, minimal beard growth, no hairline recession, no acne and significantly smaller prostates. Finasteride clinical research and development leads viewed genetic 5ar2 deficiency as a predictive model for the chronic inhibition of the 5ar2 enzyme in the adult male ​(Stoner, 1990)​ and that enzymatic inhibition with finasteride would mimic a genetic 5ar2 deficiency ​(GORMLEY et al., 1990)​. Without consideration as to the devastating outcomes for a subset of consumers, finasteride appears to be tolerated in most men.

Finasteride exhibits a highly unusual and nonlinear dose-response. Maximum DHT suppression is achieved after a single 1mg dose. It is markedly suppressive of DHT at all daily doses between 0.04 and 100mg over two weeks. Steady-state DHT levels were reduced to between 0.1-0.15ng/ml at all doses tested by Gormley et al, with DHT levels returning to pre-treatment levels within 14 days of cessation ​(GORMLEY et al., 1990)​. 0.05 to 5mg finasteride produces a 60% reduction in DHT in scalp skin. Similarly, a dose of approximately 0.2 mg of finasteride is not appreciably different to 5mg in terms of serum DHT reduction, suggesting this drug is profoundly effective at low doses ​(Frankel, 1999)​. Preferentially binding to the 5ar2 enzyme though with a notable lesser effect on 5ar1, finasteride is a pseudo-irreversible mechanism-based inhibitor that is exceptionally potent, specific, and unusually efficient. The enzyme-bound inhibitor complex follows parallel reaction coordinates that proceed through closely related enolate intermediates as testosterone’s reduction to DHT, with the two reactions proving divergent in the final step, as detailed by Bull et al ​(Bull et al., 1996)​.

No meaningful assessment of lasting sexual dysfunction was published during the clinical development of finasteride or dutasteride ​(Kiguradze et al., 2017)​. Meta-analysis of 34 clinical trials of Finasteride for use in androgenic alopecia discovered serious flaws, poor quality reporting and systematic bias ​(Belknap et al., 2015)​. None of the 34 articles considered had adequate safety reporting. Of 25 clinical trial reports with a control arm, none reported on blinding adequacy. 18 publications (53%) disclosed authors with conflicts of interest, while 19 articles (56%) received funding from a pharmaceutical manufacturer of finasteride. 12 articles (35%) did not disclose their funding. Nonsexual adverse drug events were not reported in 28 articles. One report found a clinically and statistically significant increase in Beck Depression Inventory Scores after exposure to finasteride but did not adequately assess adverse effects other than depression. Noting the flaws in reporting raised by Belknap, Lee et al. meta-analysed fifteen trials and nevertheless concluded a 1.55 fold increased risk of sexual dysfunction including erectile dysfunction, loss of libido and ejaculatory dysfunction with oral use of finasteride ​(Lee et al., 2018)​.

The typical physiological response to finasteride in animals and humans is not sufficient to account for PFS, its remarkable dose-independent severity, or the common worsening and progression following withdrawal. However, it is important that significant basic science evidence illustrates finasteride interacts with the broad physiological systems affected in PFS ​(Irwig & Kolukula, 2011)​. Use of finasteride is an identified risk factor for male infertility ​(Samplaski et al., 2019)​ and has been associated with a variably reversible depletion in sperm count in humans at 5mg and 1mg doses ​(Amory et al., 2007; Samplaski et al., 2013)​. Recent animal research reveals not only lasting decreases in fertility parameters in finasteride exposed animals ​(Garcia et al., 2012)​, but a negative impact on the fertility of the next generation ​(Kolasa-Wolosiuk et al., 2015; Kolasa-Wołosiuk et al., 2018, 2019)​. Reduced androgen levels in the offspring of finasteride treated adult male rats have been noted as similar to those reported in studies exploring the effects of prenatal exposure to the antiandrogenic endocrine disruptors flutamide and vinclozolin ​(Kolasa-Wołosiuk et al., 2019; Ostby et al., 1999)​. In gerbils, low doses of Finasteride have been demonstrated to cause structural alterations in the prostates of both sexes, as well as lasting upregulation of the AR in the prostate epithelium of intrauterine exposed males, suggested to be a compensatory response to the low available DHT ​(Maldarine et al., 2019)​. 5alpha reductase inhibition induces erectile dysfunction in rats that is not fully reversed by washout ​(Öztekin et al., 2012; Pinsky et al., 2011)​. Histopathological evidence of marked atrophic changes in prostatic epithelial tissues, loss of penile smooth muscle content and prominent collagen deposition in penile cavernosal tissues has been reported in rats treated with either Finasteride or Dutasteride ​(Sahin Kilic et al., 2018; Shen et al., 2003; Zhang et al., 2013)​, suggesting direct deleterious effects on the penis and on erectile function.

Rats subchronically treated with finasteride for 20 days showed depressive behaviour and hippocampal alterations one month after withdrawal ​(Diviccaro et al., 2019)​. Additionally, disruption of neurosteroids and steroid receptors, including an upregulation of the AR in the cerebral cortex, persisted a month after 20 days of low-dose finasteride treatment in rats, suggesting lasting structural and functional consequences on brain function ​(Giatti et al., 2015)​. Finasteride has broad consequences upon the formation of centrally active steroids and neurosteroids ​(Soggiu et al., 2016; Abdulmaged M. Traish, 2018)​. Neurosteroids are important to a range of central functions including HPA regulation and their dysregulation has a determinant role in neuropsychological abnormalities ​(Belelli & Lambert, 2005; Calogero et al., 1998; Camille Melón & Maguire, 2016; Carver & Reddy, 2013; Maguire, 2019)​. Allopregnanolone, determined to be low in the central nervous system of PFS patients ​(Melcangi et al., 2017)​, has a known role in increasing neurogenesis and neuronal cell survival, as well as reducing cell death in the hippocampus and midbrain ​(Diotel et al., 2018)​. Low or absent allopregnanolone is associated with psychological pathology including Post-Traumatic Stress Disorder (PTSD) ​(Pineles et al., 2018)​ and major depressive disorder ​(Maguire, 2019)​. Finasteride is employed experimentally to abolish the formation of neuroactive steroids including allopregnanolone in models relevant to Tourette syndrome and PTSD ​(Cadeddu et al., 2019; Nagaya et al., 2015)​.

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