! Reproductive and Nonreproductive Actions of Testosterone 2018

Reproductive and Nonreproductive Actions of Testosterone
Shalender Bhasin, Harvard Medical School, Boston, MA, United States; Research Program in Men's Health: Aging and Metabolism,
Boston, MA, United States; Boston Claude D. Pepper Older Americans Independence Center, Boston, MA, United States; and
Brigham and Women's Hospital, Boston, MA, United States
Ravi Jasuja, Translational Research and Discovery, Boston, MA, United States; Research Program in Men's Health: Aging and
Metabolism, Boston, MA, United States; Boston Claude D. Pepper Older Americans Independence Center, Boston, MA, United States;
and Brigham and Women's Hospital, Boston, MA, United States
r 2019 Elsevier Inc. All rights reserved.
Introduction
Testosterone is an important regulator of male sexual differentiation, reproductive and nonreproductive behaviors, development
of secondary sex characteristics, spermatogenesis, muscle and bone mass, erythropoiesis, and metabolism (Bhasin and Jameson,
2018; Bhasin et al., 2018). Testosterone may exert its biologic effects directly by itself or indirectly through its conversion to its two
major metabolites: 5a dihydrotestosterone (DHT) and estradiol 17b (Bhasin and Jameson, 2018; Bhasin et al., 2018). The
beneficial effects of testosterone on bone resorption, high-density lipoprotein cholesterol, atherosclerosis progression, sexual
desire, and fat mass require its conversion by CYP19A1 (aromatase) to estradiol 17b (Bhasin and Jameson, 2018; Bhasin et al.,
2018; Finkelstein et al., 2013, 2016; Vanderschueren et al., 2014). Conversion of testosterone to DHT by a family of steroid 5a-
reductase enzymes is obligatory for mediating its effects on the differentiation of the urogenital sinus and the genital tubercle
(Bhasin and Jameson, 2018; Bhasin et al., 2018). Testosterone's conversion to DHT also is believed to mediate its effects on hair
growth, scalp hair loss, prostate growth, and acne; however, it is not clear whether this conversion is obligatory for mediating its
effects on the prostate, skin, and the hair follicle (Bhasin and Jameson, 2018; Bhasin et al., 2012, 2018). Testosterone's conversion
to DHT is not required for testosterone's effects on muscle and bone, plasma lipids, and erythropoiesis (Bhasin et al., 2012; Page
et al., 2005; Amory et al., 2004).
Testosterone and the Androgen Receptor
Many actions of testosterone and DHT, including its effects on sexual differentiation of urogenital structures, spermatogenesis, muscle
and bone, and erythropoiesis, are mediated through the classical androgen receptor (AR) (Bhasin and Jameson, 2018; Bhasin et al.,
2018). As a member of the nuclear receptor superfamily, AR is a 919 amino-acid (aa), 110 kDa, ligand-inducible intracellular
transcription factor that mediates most of the biological effects of testosterone and its androgenic derivatives, including DHT (Roy
et al., 2001; Tan et al., 1988; Jenster et al., 1991; Trapman et al., 1988). AR possesses three characteristic structural domains: ligand
binding domain (LBD, CTD), DNA binding domain (DBD), and transactivation domain or N-terminus domain (NTD) (Roy et al.,
2001; Tan et al., 1988; Jenster et al., 1991; Trapman et al., 1988), The LBD in the C-terminus (690–919 aa) is highly conserved and
confers ligand specificity. The DBD (545–675 aa) also is well conserved and binds to the androgen response elements or other
transcription factors bound to the androgen response elements in the AR promoter. The NTD (1–514 aa) is not well conserved, has
been difficult of crystallize, and contains several unstructured domains. Unliganded AR is primarily located in the cytoplasm; in
response to ligand binding, AR undergoes distinct conformational changes, leading to recruitment of co-regulators and chaperone
proteins, translocation to the nucleus, dimerization, chromatin remodeling, DNA binding and eventual regulation of transcriptional
activity of AR-responsive genes (Kuil and Mulder, 1994, 1995; Tyagi et al., 2000; Kemppainen et al., 1992; Trapman et al., 1990). The
three domains of AR act in concert to conformationally gate the response to agonist or antagonist binding.
Crystal structure of C-terminus LBD of the nuclear hormone superfamily displays highly conserved arrangement of 12 a helices
(Sack et al., 2001; Pereira de Jésus-Tran et al., 2006; Bohl et al., 2007). While AR contains 11 helices, they are still numbered from 1
to 12 (helix 2 is skipped) to reflect the shared functional organization with helix 12 acting as a mobile, conformational gate.
Ligand binding is associated with significant rearrangement in the immediate vicinity of the involved residues as well as in distant
residues in other domains. The LBD is attached to the 80 aa DBD organized in two zinc-coordinated, tetra-cys sequence repeats
through a hinge region (Verrijdt et al., 2003, 2006). The DBD binds with high affinity to the androgen response elements (AREs) to
trigger transcriptional activity. While AR shares affinity for consensus reads 50 -TGTTCT-30 (clARE) with other nuclear receptors,
such as GR and PR, it also has selective ARE (selARE), including PB-ARE2 and Slp-HRE2. These interactions of the DBD and ARE
regulate the recruitment of enhancers/promoters to the macromolecular transcriptional assembly (Cato et al., 1987; Schoenmakers
et al., 2000). The crystal structures of liganded LBD and DBD have been described, but no crystallographic or solution NMR
structures have been solved for the NTD or its fragments. It is conceivable that the conformational flexibility of NTD enables intra-
and interdomain steric interactions.
AR utilizes two activation function regions located in the N-terminal domain (AF-1) and the C-terminal LBD (AF-2). These
surfaces regulate NTD/CTD interaction as well as the recruitment of co-activator and co-repressor proteins in a ligand-specific
manner (Heinlein and Chang, 2002; Bevan and Parker, 1999; Heemers and Tindall, 2007; Estébanez-Perpiñá et al., 2007). The AR
Encyclopedia of Endocrine Diseases, Second Edition, Volume 2 doi:10.1016/B978-0-12-801238-3.65412-0 721

722 Reproductive and Nonreproductive Actions of Testosterone
AF-2 plays two functional roles: (a) in the unliganded state, it associates with FxxLF (residues 23–27), WxxLF (residues 433–437)
motifs observed in the NTD to keep the AR in an inactive conformation; and (b) in the ligand-bound state, it recruits coregulators
that possess LxxLL and FxxLF motifs, including p160 family, ARA55, ARA55, ARA70, NCoRs, and SRCs. Selective recruitment of the
coregulators elicits ligand-specific, AR mediated transcriptional activity. Within the AR-AF1, two transcription activation units, Tau-
1 and Tau-5 have been described (Jenster et al., 1995). The presence of both Tau-1 and Tau-5 is obligatory and sufficient for activity
of the isolated AR-NTD and the full-length AR; mutations in Tau-1/Tau-5 render the AR protein inactive.
Collectively, the transcriptional activity of AR is regulated by a spatiotemporal interplay between domains and motifs. Ligand
binding and coregulator protein-induced conformational dynamics enable the domains to exhibit multiple functional roles.
Modulation of Testosterone’ Bioavailability and Action by Binding Proteins
Circulating testosterone is bound with high affinity to sex hormone–binding globulin (SHBG) (30%–45% in men and 70% in
women) and with substantially lower affinity to albumin (50%–68% in men and B25% in women), cortisol binding globulin,
and orosomucoid; only 1%–4% of circulating testosterone is in the unbound or free form (Fig. 1) (Bhasin and Jameson, 2018;
Bhasin et al., 2018; Goldman et al., 2017; Zakharov et al., 2015). Free testosterone refers to the circulating unbound fraction of
testosterone; according to the free hormone hypothesis, this is the fraction of circulating testosterone that is able to cross the cell
membrane and exert biologic effect. The term bioavailable testosterone refers to the fraction of circulating testosterone that is not
bound to SHBG, and reflects the view that albumin-bound testosterone may dissociate at the capillary level, especially in tissues
and organs with long transit time such as the liver and brain, and become “bioavailable” (Bhasin and Jameson, 2018; Bhasin et al.,
2018; Goldman et al., 2017). Under certain situations, SHBG may transport testosterone intracellularly through a megalin-
mediated endocytic process (Goldman et al., 2017). The binding proteins may regulate the transport, bioavailability, and clearance
of testosterone and modulate its biologic effects.
The Effects of Testosterone on Sexual Function
Testosterone regulates many domains of sexual function, including sexual desire; spontaneous sexual thoughts and fantasies;
attentiveness to erotic cues; the duration, magnitude, and frequency of nocturnal penile erections; volume of ejaculate; and, overall
sexual activity (Table 1) (Bhasin et al., 2007; Bhasin and Basson, 2016). Davidson and colleagues established that the primary role
of testosterone is to increase sexual motivation and thoughts; their studies demonstrated that hypogonadal men experienced fewer
sexual thoughts and fantasies, fewer spontaneous erections, and lower overall sexual activity than eugonadal men (Kwan et al.,
1983). However, hypogonadal men and eugonadal men exhibited similar erectile responses to visual erotic stimuli. When
androgen-deficient men were treated with testosterone, the frequency of sexual fantasies and thoughts, number of spontaneous
erections, and overall sexual activity increased (Kwan et al., 1983). However, their erectile response to visual erotic stimuli did not
change. These pioneering experiments by Davidson led to the prevalent view that spontaneous but not stimulus-induced erections
are androgen-dependent. The primary role of testosterone is to increase sexual motivation and thoughts (libido).
Fig. 1 The regulation of the bioavailability of circulating testosterone by its cognate binding proteins. Most of the circulating testosterone is
bound to at least one of four binding proteins: sex-hormone binding globulin (SHBG), albumin, cortisol binding globulin, and albumin, and only
2%–4% of circulating testosterone is free. Testosterone binds with high affinity to SHBG and with substantially lower affinity to albumin, CBG, and
orosomucoid. The term bioavailable refers to that fraction of circulating testosterone which is not bound to SHBG and reflects the belief that non-
SHBG bound testosterone, being bound with low affinity to albumin can dissociate at the capillary level and become “bioavailable.”
Reproductive and Nonreproductive Actions of Testosterone 723
Table 1 Effects of testosterone on sexual function in men
• Increases the frequency of spontaneous sexual thoughts and sexual fantasies

• Increases attentiveness to erotic cues
• Increases the frequency, duration, and magnitude of nighttime erections
• Increases the frequency of spontaneous erections
• Increases overall sexual activity
• Improves libido, erectile function, satisfaction with intercourse, and overall sexual activity in hypogonadal men
Randomized large trials of testosterone have shown that testosterone treatment of hypogonadal men with low libido improves
libido, erectile function, and overall sexual activity more than placebo (Steidle et al., 2003; Brock et al., 2016; Cunningham et al.,
2016; Snyder et al., 2016); systematic reviews and meta-analyses have confirmed these findings (Corona et al., 2014; Boloña et al.,
2007; Jain et al., 2000). Testosterone does not improve sexual function and activity in men who do not have low testosterone
levels (Basaria et al., 2015).
Testosterone replacement therapy does not improve ejaculatory function in men with low testosterone levels and ejaculatory
dysfunction (Paduch et al., 2015). There have been no randomized trials of testosterone in men with orgasmic disorders.
Testosterone regulates a number of processes that culminate in penile erection (Lugg et al., 1995; Prigo-Rocha et al., 1993;
Chamness et al., 1995; Giuliano et al., 1993; Reilly et al., 1997a,b; Heaton and Varrin, 1994; Shabsigh et al., 1998; Mills and Lewis,
1999; Mills et al., 1998). Testosterone regulates nitric oxide synthase expression and activity in the cavernosal smooth muscle of
rats (Lugg et al., 1995; Prigo-Rocha et al., 1993; Chamness et al., 1995). There is additional evidence that non-NO-dependent
pathways may also be androgen sensitive in the erectile response (Giuliano et al., 1993; Reilly et al., 1997a,b; Heaton and Varrin,
1994). Androgens exert a trophic effect on cavernosal smooth muscle (Shabsigh et al., 1998). Castration results in impaired erectile
response to central and peripheral stimulation and a decrease in penile tissue concentration of nitric oxide synthase-containing
nerves; testosterone replacement reverses these abnormalities (Heaton and Varrin, 1994). Testosterone has trophic effects in
maintaining the mass of the bulbospongiosus and ischiocavernosus muscles; the contraction of these muscles contributes to the
achievement of peak rigidity just prior to ejaculation (Mills and Lewis, 1999). Testosterone enhances blood flow into the penis
(Mills and Lewis, 1999; Mills et al., 1998; Aversa et al., 2003). Furthermore, during ganglionic stimulation, veno-occlusion fails to
occur in castrated rats (Mills et al., 1998; Fournier et al., 1987). Collectively, these data indicate that testosterone plays an
important role in regulating erectile mechanisms at multiple levels.
Androgen deficiency and erectile dysfunction are two independently distributed conditions, each with a distinct pathophysiology.
However, the two conditions often overlap, particularly in older individuals and in those with comorbid conditions (Korenman et al.,
1990). Phosphodiesterase 5 inhibitors can improve erectile function in eugonadal and hypogonadal men (Tsertsvadze, 2009).
Randomized controlled trials have failed to demonstrate further improvements in erectile function with the addition of testosterone
to an optimized regimen of phosphodiesterase 5 inhibitors (PDE5I) (Spitzer et al., 2012; Buvat et al., 2011). However, we do not
know whether testosterone replacement therapy would improve subsequent erectile response to PDE5Is.
Anabolic Effects on the Skeletal Muscle (Table 2)
Testosterone is a potent anabolic hormone which increases skeletal muscle mass, maximal voluntary muscle strength, and muscle power in
healthy men (Bhasin et al., 1996, 2001). Testosterone replacement also increases fat-free mass and maximal voluntary strength, and
decrease fat mass in healthy hypogonadal men, HIV-infected men with weight loss, and in men with chronic obstructive lung disease or
end stage renal disease (Bhasin et al., 1997, 2000, 2005a; Grinspoon et al., 1998; Casaburi et al., 2004; Wang et al., 2000). Randomized
clinical trials in middle-aged and older men with low or low-normal testosterone concentrations have also demonstrated greater gains in
lean body mass and grip strength with testosterone administration compared with placebo (Bhasin et al., 2005b; Snyder et al., 1999; Page
et al., 2005; Kenny et al., 2001, 2002; Blackman et al., 2002; Basaria et al., 2010; Travison et al., 2011; Srinivas-Shankar et al., 2010; Storer
et al., 2008, 2017; Nair et al., 2006; Emmelot-Vonk et al., 2008; Liverman and Blazer, 2004). The loss of fat mass induced by testosterone
therapy is distributed evenly between appendicular and trunk compartments and within each of those compartments between superficial
subcutaneous, and deep intramuscular, and visceral fat compartments (Woodhouse et al., 2004).
In spite of a clear demonstration of the gains in muscle mass and strength by testosterone administration, the effects of testos-
terone replacement on performance-based measures of physical function have been inconsistent across studies. In older men with
mobility limitation, testosterone replacement improves VO2peak (Storer et al., 2016), self-reported function, and some performance-
based measures of physical function that are more closely related to lower extremity muscle strength and power, such as stair climbing
speed and power (Basaria et al., 2010; Travison et al., 2011; Storer et al., 2008). However, testosterone's treatment effect on 6-min
walking speed and distance in randomized trials has been small, and its clinical meaningfulness remains unclear (Snyder et al., 2016).
Testosterone-induced increase in muscle strength is related to the gains in muscle mass; testosterone does not improve the specific force
of the muscle (Storer et al., 2003). Thus, testosterone administration does not improve the contractile properties of the skeletal muscle.
Testosterone administration induces muscle fiber hypertrophy and increases the cross-sectional area of both type 1 and type 2 skeletal
muscle fibers; testosterone does not change the absolute number of type 1 or type 2 muscle fibers or their relative proportion (Sinha-Hikim
Table 2 Effects of testosterone on the skeletal muscle
Effects on skeletal muscle histomorphology
• Hypertrophy of type 1 and 2 muscle fibers

• Increased mitochondrial mass and quality
• Increased number of myonuclei and satellite cells
Effects on body composition
• Increase in whole body, appendicular, and trunk lean mass

• Decrease in whole body, subcutaneous, intermuscular, and abdominal fat
Effects on measures of skeletal muscle performance
• Increased maximal voluntary muscle strength in both upper and lower extremity
muscle groups
• Increased muscle power
• No change in specific force
Effects on aerobic performance
• Attenuation of age-related decline in VO2peak
Effects on self-reported and performance-based measures of physical function
• Improvements in self-reported function, including perception of walking ability

• Improved stair climbing speed and power
• Small improvement in 6-min walking distance
et al., 2002). Testosterone increases the number of myonuclei and muscle satellite cells, but it does not alter the myonuclear domain
(Sinha-Hikim et al., 2003). Thus, the primary action of testosterone is to induce skeletal muscle fiber hypertrophy by increasing the number
of satellite cells.
Testosterone promotes the differentiation of mesenchymal progenitor cells into the myogenic lineage and inhibits their differentiation into
the adipogenic lineage (Bhasin et al., 2003; Sinha-Hikim et al., 2006; Singh et al., 2003, 2006). In addition, testosterone has been postulated to
improve net muscle protein balance by stimulating muscle protein synthesis, decreasing muscle protein degradation, and improving the
reutilization of amino acids (Ferrando et al., 2002; Urban et al., 1995). Testosterone stimulates circulating growth hormone secretion and IGF-
1 levels although circulating IGF-1 is not obligatory for mediating testosterone's effects on the skeletal muscle (Serra et al., 2011).
Testosterone's anabolic effects on the skeletal muscle are mediated largely through the classical AR and are blocked by AR
antagonists. Testosterone's binding to AR leads to a conformational change in AR, enables it to associate with other co-regulators,
including b catenin, stabilizing the latter (Singh et al., 2009). The liganded AR along with b catenin and other associated chaperon
proteins translocate into the nucleus and binds to the transcription factor TCF-4 (Fig. 2) (Singh et al., 2009). The quaternary complex
then binds specific DNA regions to regulate the transcription of Wnt-target genes including follistatin, which blocks the action of
several members of the TGF b family (Singh et al., 2009; Braga et al., 2012), including myostatin and activins (Fig. 2). Follistatin plays
an important role in mediating the anabolic effects of testosterone on the muscle; blocking follistatin action abrogates testosterone's
effects on myogenic differentiation (Braga et al., 2012). The administration of recombinant follistatin (rFst) increases muscle mass in
mice, but has no effect on prostate mass (Jasuja et al., 2014). Microarray analysis of mRNAs from prostate and levator ani of castrated
male mice treated with vehicle, testosterone, or rFst revealed that testosterone and rFst shared the regulation of many transcripts in
levator ani; however, in prostate, 593 transcripts in several growth-promoting pathways were differentially expressed after testos-
terone treatment, while rFst showed a negligible effect with only nine transcripts differentially expressed. Among pathways that were
differentially responsive to testosterone in prostate, we identified ornithine decarboxylase (Odc1), an enzyme in polyamine bio-
synthesis, as a testosterone-responsive gene that is unresponsive to rFst (Jasuja et al., 2014). When we administered testosterone with
and without a-difluoromethylornithine (DFMO), an Odc1 inhibitor, to castrated mice, DFMO selectively blocked testosterone's
effects on prostate, but did not affect testosterone's anabolic effects on the muscle (Jasuja et al., 2014). Thus, co-administration of
testosterone and an Odc1 inhibitor offers a novel therapeutic strategy for prostate-sparing anabolic therapy (Jasuja et al., 2014).
Testosterone's Effects on Erythropoiesis
Testosterone administration increases hemoglobin, hematocrit, and red cell mass (Coviello et al., 2008; Calof et al., 2005), and has
been used to treat anemia of inflammation and chronic kidney disease. Testosterone also is efficacious in correcting unexplained
anemia of aging (Roy et al., 2017) and inflammation (Guo et al., 2016). The erythropoietic effects of testosterone are related to
testosterone dose, circulating testosterone concentrations, and age (Coviello et al., 2008). Older men experience greater increments
in hemoglobin and hematocrit than younger men, after adjusting for testosterone dose (Coviello et al., 2008). Erythrocytosis is the
Fig. 2 The molecular mechanisms by which testosterone regulates the differentiation of mesenchymal progenitor cells through activation of Wnt
signaling. The effects of testosterone on mesenchymal progenitor cell differentiation are mediated largely through the activation of Wnt signaling.
After ligand binding, the androgen receptor undergoes conformation change and binds to beta catenin, stabilizing the latter, and preventing its
degradation. The AR-beta catenin complex which may include additional chaperone proteins translocated into the nucleus and after binding TCF-4
regulates a number of Wnt-target genes, including follistatin, which blocks the action of a number of TGF b family members, such as myostatin
and activins. Follistatin plays an important role in mediating the regulation of mesenchymal progenitor cell differentiation into the myogenic lineage
and inhibiting their differentiation into adipogenic lineage.
most frequent adverse event noted in testosterone trials, and is an important dose-limiting adverse effect of testosterone therapy
(Calof et al., 2005).
The mechanisms by which testosterone increases hemoglobin and hematocrit are incompletely understood. Testosterone
stimulates iron-dependent erythropoiesis through multiple mechanisms (Guo et al., 2013). Testosterone increases iron availability
and iron incorporation into the red cells by inhibiting hepcidin (Guo et al., 2013; Bachman et al., 2010, 2014). Testosterone
inhibits hepcidin transcription through its interaction with BMP-Smad signaling (Guo et al., 2013). Testosterone administration
promotes the association of liganded-AR with Smad1 and Smad4 to reduce their binding to BMP-response elements in the
hepcidin promoter in the liver (Guo et al., 2013). Testosterone increases erythropoietin production and resets the erythropoietin to
hemoglobin set point (Bachman et al., 2014). In older mice, testosterone may also improve red cell survival (Guo et al., 2014).
Effects on Bone Metabolism
Sex steroids are important contributors to sex differences in bone mass and strength, and fracture risk (Vanderschueren et al., 2014;
Khosla et al., 1998; Riggs et al., 2004). Men have greater bone mass and strength than women in part because of the greater cortical
bone acquisition during puberty (Vanderschueren et al., 2014). Testosterone increases bone mass and strength through multiple
pathways either by binding to the AR itself or indirectly through its conversion to estradiol 17b and signaling through the estrogen
receptor a (ERa) (Finkelstein et al., 2016; Vanderschueren et al., 2014). AR is expressed in the osteoblastic and osteoclastic lineages,
and by chondrocytes (see Vanderschueren et al., 2014 for an excellent review of this topic, Kasperk et al., 1989). Testosterone
promotes apoptosis of osteoclasts and exerts antiapoptotic effects on osteoblasts and osteocytes (Kousteni et al., 2001). Testos-
terone regulates the differentiation of bone progenitor cells into osteoblasts and osteoclasts and reduces the number of bone
remodeling cycles (Khosla et al., 1998; Kasperk et al., 1990). Testosterone directly stimulates periosteal bone formation; addi-
tionally, genetic studies suggest that testosterone also regulates trabecular bone via AR in osteoblasts and osteocytes, independent
of its aromatization to estradiol (Callewaert et al., 2009; Moverare et al., 2003; Venken et al., 2006). Thus, AR actions, independent
of its aromatization, contribute to greater periosteal bone formation and enhanced trabecular bone development during puberty
in male mice (Callewaert et al., 2009; Moverare et al., 2003; Venken et al., 2006). Estradiol acting via ERa in osteoblast lineage cells
regulates cortical as well as the trabecular bone mass (Vanderschueren et al., 2014; Bord et al., 2001; Syed et al., 2011; Venken et al.,
2006). Activation of ERa signaling, the dominant mediator of estrogen actions in bone, stimulates periosteal and trabecular bone
formation and inhibits endocortical and trabecular bone resorption in female mice (Vanderschueren et al., 2014; Bord et al., 2001;
Syed et al., 2011; Venken et al., 2006). Thus, both AR and ERa actions play a role in male cortical and trabecular peak bone mass
acquisition (Vanderschueren et al., 2014; Kousteni et al., 2001; Kasperk et al., 1990; Callewaert et al., 2009; Moverare et al., 2003;
Venken et al., 2006; Bord et al., 2001; Syed et al., 2011).
Testosterone also regulates bone mass and bone strength indirectly through its anabolic effects on muscle mass and muscle strength
(Vanderschueren et al., 2014). Increase in muscle mass and strength may also reduce fall propensity and reduce fracture risk.
Testosterone replacement therapy in severely hypogonadal improves areal bone mineral density (aBMD) as well as volumetric
BMD (vBMD) (Snyder et al., 2000; Katznelson et al., 1996; Benito et al., 2005; Zhang et al., 2008; Al Mukaddam et al., 2014).
Testosterone treatment of hypogonadal men improves trabecular architecture and estimated bone strength (Zhang et al., 2008; Al
Mukaddam et al., 2014; Snyder et al., 2017). Meta-analyses of randomized trials of testosterone in older men with low or low
normal levels have reported improvements in vertebral aBMD (Tracz et al., 2006). In community-dwelling older men, 65 years or
older, who had unequivocally low testosterone levels and symptoms of low libido, mobility problems or low vitality, testosterone
treatment for 1 year increased vBMD of trabecular bone in the spine more than placebo and increased estimated bone strength of
trabecular bone in the spine more than placebo (Snyder et al., 2017). Testosterone also significantly increased whole bone vBMD
and strength of the spine and trabecular and whole bone vBMD and strength of the hip (Snyder et al., 2017). Testosterone's efficacy
in reducing fracture risk in men with osteoporosis has not been studied.
Effects on Mood and Depressive Symptoms
In the TTrials, testosterone treatment had a small positive effect on mood and depressive symptoms (Snyder et al., 2016). The
magnitude of each of these effects was small and their clinical meaningfulness remains unclear.
Multiple lines of evidence support the hypothesis that a major subset of persistent depressive disorder (PDD) in men—defined
as mid-life-onset, low-grade, chronic depression—might be responsive to testosterone replacement (Seidman, 2003; Almeida et al.,
2008). Epidemiological studies have demonstrated an association between lower testosterone levels and chronic low-grade
depression (Seidman et al., 2002; Markianos et al., 2007; Shores et al., 2004). Testosterone, whether administered alone or as an
augmentation strategy in conjunction with traditional antidepressant therapy, tends to be ineffective in men with major depressive
disorder (MDD) (Seidman et al., 2001, 2005; Orengo et al., 2005; Pope et al., 2010). However preliminary evidence suggests that
testosterone therapy can improve depressive symptoms in men with low-grade, late-onset depression (Seidman et al., 2009; Shores
et al., 2009; Bloch et al., 1999). These data suggest that testosterone replacement might be efficacious as a treatment for this
subgroup of men with late-onset, low-grade PDD (previously referred to as dysthymia in DSM-4), but not in men with MDD.
Testosterone's Effects on Reproductive and Nonreproductive Behaviors (Table 3)
Testosterone regulates the expression of many sexually dimorphic reproductive behaviors in rodents and higher mammals,
including mounting and ejaculation (Fielder et al., 1989; Bhasin et al., 1988; Muller, 2017). Testosterone also influences territorial
scent marking, and promotes aggression and competition among males of many mammalian species at the time of mate selection
(Fielder et al., 1989; Steensland et al., 2005; Fischer et al., 2007; Carrillo et al., 2011; Le Greves et al., 1997). Androgens induce both
offensive and defensive behaviors in rats, hamsters, and nonhuman primates, and activate the associated signaling molecules and
their receptors (Steensland et al., 2005; Fischer et al., 2007; Carrillo et al., 2011; Le Greves et al., 1997). Rats treated with androgens
exhibit enhanced dominant behavior in a competition test compared to controls (Steensland et al., 2005; Fischer et al., 2007;
Carrillo et al., 2011; Le Greves et al., 1997; Henderson et al., 2006; Kindlundh et al., 2003; Schwartzer and Melloni, 2010; Breuer
et al., 2001). The brain pathways associated with aggression include neural circuits that utilize signaling by excitatory amino acid
systems (e.g., glutamate, GABA), and monoaminergic and peptidergic neurotransmitters (Fischer et al., 2007; Carrillo et al., 2011;
Le Greves et al., 1997; Henderson et al., 2006; Kindlundh et al., 2003; Schwartzer and Melloni, 2010). The key brain regions
involved in aggressive behavior include the anterior hypothalamus, periaqueductal gray, and amygdaloid nuclei, particularly the
central and medial amygdala. Androgens enhance ß endorphin in the VTA and may thereby activate the brain reward system (see
Wood, 2008 for a review). Rats and mice display conditioned place preference to testosterone and male hamsters will self-
administer testosterone to the point of death (Wood, 2008; Arnedo et al., 2000). Interestingly, the opioid antagonist naltrexone
can block testosterone self-administration in hamsters (Johansson et al., 2010). These observations, combined with others, suggest
that opioidergic mechanisms may be involved in the hedonic pathway to androgen dependence (Wood, 2008; Arnedo et al., 2000;
Johansson et al., 2010).
Table 3 Effects of testosterone on reproductive and nonreproductive behaviors in mammals
Reproductive behaviors
• Promotes mounting and ejaculation, reduces latency to mount, and ejaculate and post-ejaculatory interval
• Promotes competition and aggression among males of many mammalian species
Nonreproductive behaviors
• Promotes territorial scent marking

• Induces offensive and defensive behaviors
• Enhances dominant behavior
• Conditioned place preference for testosterone
Testosterone Effects on Cognition
Sex differences between men and women in several domains of cognition have supported the hypothesis that testosterone exerts
domain-specific effects on cognition (Maccoby and Jacklin, 1974). Although there are substantial interindividual differences in
performance, as a group, on average, men perform better than women in tests of visuospatial cognition and women perform better
than men in tests of verbal memory and verbal fluency (Maccoby and Jacklin, 1974; Shute et al., 1983). Women with congenital
adrenal hyperplasia with high testosterone levels score higher on tests of spatial cognition and individuals with androgen insensitivity
syndrome perform worse on tests of spatial cognition than age- and sex-matched controls (Maccoby and Jacklin, 1974).
Androgen receptors are expressed in specific brain regions (Simerly et al., 1990), and some organizational effects of testosterone
on brain are mediated through AR-mediated mechanisms (Lustig, 1994). Androgens stimulate neurite arborization, facilitating
intercellular communication (Lustig, 1994). Testosterone may also exert nongenomic effects and affect neurotransmitters such as
serotonin, dopamine, acetylcholine, and calcium signaling (Fernández-Balsells et al., 2010; Khaw and Barrett-Connor, 1992). The
nongenomic effects of testosterone are less well characterized than genomic effects. Testosterone also is aromatized to estradiol
within brain regions, and some effects of testosterone may be mediated through estrogen receptor. Testosterone's organizational
effects on reproductive and nonreproductive behaviors during critical development windows of sexual differentiation have been
well characterized in preclinical models.
Intervention trials have provided inconsistent data on the effects of testosterone therapy on verbal memory and visual-spatial
cognition (Cherrier et al., 2001). In older men with low testosterone levels, testosterone treatment compared with placebo did not
improve delayed paragraph recall, visual memory, spatial ability, executive function, subjective memory complaints, or immediate
paragraph recall (Resnick et al., 2017). Testosterone also did not improve measures of cognition in older men with minimal
cognitive impairment (Resnick et al., 2017). It is not known whether testosterone can prevent progression from minimal cognitive
impairment to dementia and retard the development of Alzheimer disease.
Testosterone's Effects on Metabolic and Cardiovascular Risk
We do not know whether testosterone replacement increases the risk of major adverse cardiovascular events in hypogonadal men
(Liverman and Blazer, 2004; FDA, 2017; EMA, 2018). Testosterone exerts a number of physiologic effects, some of which may be
beneficial and some potentially deleterious to the cardiovascular system (Table 4) (Liverman and Blazer, 2004). Testosterone acts a
vasodilator by inhibition of L-type calcium channels, resulting in increased coronary and penile blood flow; testosterone acts like the
dihydropyridine calcium channel blockers to reduce calcium influx into vascular smooth muscle, thereby promoting vasodilation
(Scragg et al., 2004). Testosterone decreases whole body, subcutaneous and intra-abdominal fat (Bhasin et al., 2001; Woodhouse et al.,
2004); it reduces vascular reactivity and improves endothelial function; and, it shortens QTc intervals (Gagliano-Jucá et al., 2017).
The potential deleterious effects of testosterone that could increase the risk of cardiovascular events, include the increase in
hematocrit (Calof et al., 2005; Fernández-Balsells et al., 2010), a small but significant reduction in plasma HDL cholesterol
(Fernández-Balsells et al., 2010), induction of platelet aggregation presumably via stimulation of thromboxane A2, and sodium
and water retention, which could contribute to edema formation or exacerbation of preexisting heart failure. In preclinical models,
testosterone promotes smooth muscle proliferation and increases VCAM expression. Testosterone increases the levels of both
prothrombotic as well as antithrombotic factors.
Testosterone has been shown to retard atherosclerosis in some preclinical models but not in others. Testosterone induces
myocardial hypertrophy in some mouse strains, but not in others. Some randomized trials have reported increase in blood
pressure, but these data are not consistent across trials.
The effects of testosterone on insulin sensitivity also are inconsistent across trials. Low total, but not free, testosterone levels
have been associated with central adiposity, insulin resistance and diabetes risk (Khaw and Barrett-Connor, 1992; Haffner, 1996;
Makhsida et al., 2005; Muller et al., 2004). Total testosterone concentrations are highly correlated with SHBG concentrations and
SHBG concentrations are independently associated with the risk of diabetes and metabolic syndrome (Ding et al., 2009; Bhasin
et al., 2011). In fact, free testosterone levels are either not associated or only weakly associated with metabolic risk (Bhasin et al.,
2011). In models of severe androgen deficiency, such as in men receiving androgen deprivation therapy, or men experimentally
rendered hypogonadal by administration of GnRH agonists or antagonists, there is an acute worsening of insulin sensitivity
(Pitteloud et al., 2005). However, the effects of testosterone on measures of insulin sensitivity in intervention trials have been
inconsistent in RCTs (Singh et al., 2002).
The relationship of testosterone and coronary artery disease and cardiovascular events in cross-sectional and prospective cohort
studies has been inconsistent (Ohlsson et al., 2011; Srinath et al., 2015; Khazai et al., 2016; Corona et al., 2011). Some epide-
miologic studies have reported a negative relationship between testosterone concentrations and common carotid artery intima-
media thickness, a measure of subclinical atherosclerosis (Srinath et al., 2015; Khazai et al., 2016).
Low total testosterone levels have been associated with higher risk of all-cause mortality, especially cardiovascular mortality (Araujo
et al., 2011). Epidemiological studies can only show association but cannot prove causality; reverse causality cannot be excluded. It is
possible that testosterone is a marker of health, and those who are higher risk of dying have lower testosterone levels.
The number of venous thromboembolic events in randomized trials of testosterone have been too few to permit strong
inferences. Some retrospective analyses have suggested an increased risk of venous thromboembolism during the first few months
Table 4 Potential beneficial and deleterious physiologic effects of testosterone on the

cardiovascular system
Potentially beneficial effects
• Increased coronary blood flow

• Decreased whole body and abdominal fat mass
• Improved vascular reactivity
• Reduced QTc interval
Potentially deleterious effects
• Increased hematocrit
• Lowering of HDL cholesterol
• Increased platelet aggregation
• Increased vascular smooth muscle proliferation
• Salt and water retention
Inconclusive or inconsistent effects
• Myocardial hypertrophy in some strains but not others

• Retards early atherogenesis in some animal models but not in others
• Increases the circulating levels of both prothrombotic and antithrombotic factors
• No consistent increase in blood pressure in randomized trials
of testosterone therapy (Baillargeon et al., 2015; Martinez et al., 2016). Most cases of venous and arterial thrombotic events have
occurred in men with preexisting hypercoagulable condition (Glueck et al., 2016).
Several retrospective analyses of the association of testosterone administration with mortality and cardiovascular events have been
published, but these studies have yielded conflicting results (Vigen, 2013; Sharma et al., 2015; Anderson et al., 2016; Muraleedharan et al.,
2013; Cheetham et al., 2017; Borst et al., 2014; Alexander et al., 2017). These retrospective analyses of electronic medical records suffer
from many limitations: the inclusion of heterogeneous study populations; differences in the duration of intervention; the use of variable
definitions; and a lack of prospective ascertainment of cardiovascular outcomes (Vigen, 2013; Sharma et al., 2015; Anderson et al., 2016;
Muraleedharan et al., 2013; Cheetham et al., 2017; Borst et al., 2014; Alexander et al., 2017). Treatments indications, treatment regimens,
on-treatment testosterone levels and exposure differed among studies (Vigen, 2013; Sharma et al., 2015; Anderson et al., 2016; Mur-
aleedharan et al., 2013; Cheetham et al., 2017; Borst et al., 2014; Alexander et al., 2017). They also suffered from a potential for residual
confounding in that the patients assigned to testosterone therapy differed from comparators in baseline cardiovascular risk factors. A
number of meta-analyses have examined the association between testosterone replacement and cardiovascular events, major cardio-
vascular events, and death in RCTs (e.g., Alexander et al., 2017). Most of these meta-analyses have not shown a statistically significant
association between testosterone and cardiovascular events, major cardiovascular events, or deaths (Alexander et al., 2017). These meta-
analyses are limited by the heterogeneity of randomized trials included in these analyses (Kloner et al., 2016). The trials also were
heterogeneous with respect to eligibility criteria, testosterone dose and formulation, and intervention durations. The variable quality of
adverse event recording in clinical trials has been well-documented, and was particularly apparent in these trials. The small size of many
trials and the inclusion of pilot studies with very small sample sizes was another constraint. Cardiovascular outcomes were not
prespecified, they were often defined post-hoc, and were of varying clinical significance. The major cardiovascular events were not
adjudicated, not specified prospectively, and the total number of major cardiovascular events was too small to draw strong inferences.
There are no published randomized trials that were long enough or large enough to determine the effects of testosterone
therapy on CV events. In two RCTs in middle-aged and older men, testosterone replacement therapy did not affect the rate of
atherosclerosis progression assessed using common carotid artery intima-media thickness or coronary artery calcium scores
(Basaria et al., 2015; Budoff et al., 2017). In the TTrials, testosterone treatment was associated with a greater increase in the volume
of noncalcified plaque volume (Budoff et al., 2017).
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Reproductive and Nonreproductive Actions of Testosterone

Testosterone and the Androgen Receptor

Encyclopedia of Endocrine Diseases, Second Edition, Volume 2 doi:10.1016/B978-0-12-801238-3.65412-0 721

Modulation of Testosterone’ Bioavailability and Action by Binding Proteins

The Effects of Testosterone on Sexual Function

Table 1 Effects of testosterone on sexual function in men

• Increases the frequency of spontaneous sexual thoughts and sexual fantasies

Anabolic Effects on the Skeletal Muscle (Table 2)

Table 2 Effects of testosterone on the skeletal muscle

Effects on skeletal muscle histomorphology

• Hypertrophy of type 1 and 2 muscle ﬁbers

Effects on body composition

• Increase in whole body, appendicular, and trunk lean mass

• Attenuation of age-related decline in VO2peak

Effects on self-reported and performance-based measures of physical function

• Improvements in self-reported function, including perception of walking ability

Testosterone's Effects on Erythropoiesis

Effects on Bone Metabolism

Effects on Mood and Depressive Symptoms

Testosterone's Effects on Reproductive and Nonreproductive Behaviors (Table 3)

Table 3 Effects of testosterone on reproductive and nonreproductive behaviors in mammals

• Promotes territorial scent marking

Testosterone Effects on Cognition

Testosterone's Effects on Metabolic and Cardiovascular Risk

Table 4 Potential beneﬁcial and deleterious physiologic effects of testosterone on the

Potentially beneﬁcial effects

• Increased coronary blood ﬂow

• Myocardial hypertrophy in some strains but not others

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