Obesity’s role in secondary male hypogonadism: a review of pathophysiology and management issues

Abstract

Obesity and male hypogonadism are both associated with one another. Moreover, male hypogonadism can serve as a risk factor for obesity while obesity can serve as a risk factor for male hypogonadism. There has been little research regarding obesity and its reduction on that of gonadal function. Lifestyle factors as well as other factors have been attributed to the development of obesity which can induce gonadal dysfunction. Therefore, the treatment of male hypogonadism is of great interest for both providers and patients. The future of hypogonadism therapy may exist with the development of aromatase inhibitors that can minimize undesired effects and allow the benefits of androgens. Testosterone treatment can lead to compromised fertility and addiction. Aromatase allows for the peripheral conversion of androgens into estrogens resulting in the inhibition of gonadotropin production. Therefore, aromatase inhibitors can be used instead to increase gonadotropin secretion. There is growing evidence that aromatase inhibitors can improve the fertility and raise testosterone levels.

Full text

MEDICINE
Obesity’s role in secondary male hypogonadism: a review
of pathophysiology and management issues
Omar Seyam
1
&Jason Gandhi
1,2
&Gunjan Joshi
3
&Noel L. Smith
4
&Sardar Ali Khan
1,5
Accepted: 20 February 2019
#Springer Nature Switzerland AG 2019
Abstract
Obesity and male hypogonadism are both associated with one another. Moreover, male hypogonadism can serve as a risk factor for
obesity while obesity can serve as a risk factor for male hypogonadism. There has been little research regarding obesity and its
reduction on that of gonadal function. Lifestyle factors as well as other factors have been attributed to the development of obesity
which can induce gonadal dysfunction. Therefore, the treatment of male hypogonadism is of great interest for both providers and
patients. The future of hypogonadism therapy may exist with the development of aromatase inhibitors that can minimize undesired
effects and allow the benefits of androgens. Testosterone treatment can lead to compromised fertility and addiction. Aromatase
allows for the peripheral conversion of androgens into estrogens resulting in the inhibition of gonadotropin production. Therefore,
aromatase inhibitors can be used instead to increase gonadotropin secretion. There is growing evidence that aromatase inhibitors
can improve the fertility and raise testosterone levels.
Keywords Aromatase .Hypogonadism .Obesity .Male erectile dysfunction .Androgens .Estrogens .Pituitary gland
Introduction
There is an increased prevalence of hypogonadism in the male
population that has been described in several studies. A con-
sistent theme among these studies is that as men age,
hypogonadism increases. Physicians often prescribe testoster-
one to obese men with hypogonadism; however, it is wiser to
provide aromatase inhibitors to prevent this instead. Also, pa-
tients may become addicted to testosterone, and eventually
physiological response such as libido and erectile dysfunction
(ED) will gradually decline due to high aromatase activity.
Therefore, patients may become refractory to testosterone
treatment.
Methodology
An extensive search was performed on PubMed and
MEDLINE for any published literature on the role of aroma-
tase in adult male for obesity-associated hypogonadism.
Although there was no date restriction on the search, we
placed an emphasis on the past 5 years. No specific exclusion
criteria were set. Publication quality was assessed using the
relative citation ratio derived from iCite bibliometrics. We
selected papers that revealed information regarding the phys-
iology of androgen and aromatase production, obesity and
aromatase function regarding hypogonadism, aromatase in-
hibitors, other treatment modalities for obesity-induced
hypogonadism, complication of androgen replacement on
prostate, and addiction to anabolic steroids.
This article is part of the Topical Collection on Medicine
*Sardar Ali Khan
skysalik@gmail.com
1
Department of Physiology and Biophysics, Renaissance School of
Medicine, Stony Brook University, Stony Brook, NY, USA
2
Medical Student Research Institute, St. George’s University School
of Medicine, West Indies, Grenada
3
Department of Internal Medicine, Stony Brook Southampton
Hospital, Southampton, NY, USA
4
Foley Plaza Medical, New York, NY, USA
5
Department of Urology, Renaissance School of Medicine, Stony
Brook University, Stony Brook, NY, USA
SN Comprehensive Clinical Medicine
https://doi.org/10.1007/s42399-019-00056-7

Results and Discussion
Physiology of androgen production
Male androgen production is managed by the release of folli-
cle stimulating hormone (FSH) and luteinizing hormone (LH)
by the anterior pituitary gland. The process begins with the
hypothalamus secreting gonadotrophin releasing hormone
(GnRH) into the portal blood leading to the anterior pituitary
gland. In response to GnRH, the anterior pituitary gland re-
leases both FSH and LH into the bloodstream to be
transported to the testes [1,2].
Within the interstitial space surrounding the seminiferous
tubules, the Leydig cells will secrete androgen and testoster-
one, in response to stimulation caused by LH [1]. The enzyme
5α- reductase converts testosterone found in the adrenal
glands, prostate, hair follicles, and testes into dihydrotestos-
terone (DHT). A negative feedback loop between the testes
and the pituitary gland manages androgen production to stay
within normal physiological levels [3]. High levels of DHT or
testosterone sensed by the anterior pituitary gland diminish
LH surge to downregulate testosterone and DHT levels [2].
FSH stimulates the Sertoli cells within the seminiferous
tubules causing the secretion of androgen-binding protein
(ABP). ABP binds with testosterone within the seminiferous
tubules to promote spermatogenesis. ABP is known to also
link with DHT and 17-beta-estradiol. A majority of testoster-
one not bound to ABP would be bounded to sex-hormone-
binding globulin (SHBG). [3] Remaining testosterone not
bound to ABP or SHBG circulates the blood in an unbound
form to either be transferred to the tissues or converted into an
inactive form that will eventually be secreted [2]. A small
percentage of testosterone will be converted into estradiol by
the enzyme aromatase cytochrome P450 [2]. The generated
sperm cells will be found in the lumen of the seminiferous
tubules. The Sertoli cells also secretes inhibin in response to
FSH stimulation. Inhibin acts as a negative feedback signal to
the anterior pituitary gland. High levels of inhibin cause the
anterior pituitary gland to decrease the rate of FSH secretion,
resulting in the decrease of Sertoli cell stimulation and sper-
matogenesis [4].
Hypogonadism
Male hypogonadism is the failure to produce sufficient testos-
terone for physiological use. Hypogonadism is commonly
found in older males due to their age being a natural detriment
in testosterone production. Males with HIV and obesity also
seem to prone to hypogonadism [5–8]. Testosterone is a vital
steroid for males as it plays roles in vast physiological func-
tions such as testicular function, hair growth, nitrogen reten-
tion, development of bone density, development and distrib-
uting muscle mass, metabolism of fat, development of
secondary sexual characteristics, and psychological factors
dictating personality such as aggression, self-esteem, and mo-
tivation [1,5–10]. A significant decrease in testosterone, such
as one due to hypogonadism, significantly decreases the qual-
ity of life since multiple physiological mechanisms will not be
operating at normal levels.
Hypogonadism can occur as early fetal development. A
genetically male child with hypogonadism may be born with
either underdeveloped genitals, ambiguous genitals, or even
female genitals [9,10]. This can be explained due to dihydro-
testosterone (DHT), a converted form of testosterone, which is
vital in external genitalia development for males. A shortage
of DHT may disrupt male sexual development before birth.
Hypogonadism that occurs in males at pubertal ages may ex-
perience a delay or complete lack of puberty and develop-
ment. Individuals would experience impaired penis and testic-
ular growth, disproportionate limb growth in respect to their
torso, impaired growth or lack of body and facial hair, failure
in deepening of their voice, decrease in muscle mass develop-
ment, and gynecomastia (development of breast tissue)
[9–13].
The effects on adult males range from psychological to
emotional and sexual, the most effected attribute of life dis-
turbed by acquiring hypogonadism. Individuals exhibit a de-
crease in bone mineral density, muscle mass, body and facial
hair, osteoporosis, gynecomastia, hot flashes, depression, lack
of interest, difficulty concentrating, accumulation of fat, tem-
poral hair recession, lack of a deepened voice, and loss of
aspects gained during puberty [9,10,14]. These symptoms
can also be seen concurrently with the sexual side effects of
hypogonadism found in Table 1.
The causes of hypogonadism can be differentiated into two
types known as primary hypogonadism and secondary
hypogonadism. Primary hypogonadism involves disease or
damage done to the seminiferous tubules themselves.
Individuals experiencing primary hypogonadism have high
concentrations of FSH and LH and/or low concentrations of
serum testosterone and/or sperm count [3,8,15–17]. Damage
to the seminiferous tubules can lead malfunction ofthe Leydig
and Sertoli cells’production of testosterone and inhibin,
Table 1 Sexual
manifestations of
hypogonadism in adult
males
Fatigue [15]
Decrease or lack of libido [16]
Lack of erections [17]
Decreased ejaculate [18]
Premature ejaculation [19]
Delayed and decreased orgasm [15]
Micropenis [20]
Erectile dysfunction [21]
Benign prostate hyperplasia [22]
Infertility [23]
SN Compr. Clin. Med.

ultimately disrupting the negative feedback loop with the an-
terior pituitary gland causing the overproduction of FSH and
LH with no check. A list of common diseases and conditions
causing primary hypogonadism can be found in Tables 2and 3.
Secondary hypogonadism suggests that disease or damage
has occurred to either the hypothalamus or the pituitary gland.
Individuals experiencing secondary hypogonadism have ei-
ther low or normal concentrations of FSH and LH and/or
low concentrations of serum testosterone and/or sperm count
[3,8,15–17]. Damage to the hypothalamus or the pituitary
gland can result in the malfunction of the negative feedback
loop with the tests resulting in the inability to differentiate
whether rate of FSH and LH should be increased or not.
Another effect of such damage would be the inability of the
hypothalamus to determine when to release GnRH causing
fluctuations in FSH and LH [17–19]. A list of common dis-
eases and conditions causing secondary hypogonadism can be
found in Table 2.
Both types of hypogonadism can be either a congenital trait
or acquired throughout life [3,5–8,15,16]. It is also possible
for both types to occur at the same time. Laboratory testing
and imagery are required in order to properly differentiate
between primary and secondary hypogonadism during diag-
nosis such as a dedicated pituitary MRI for secondary
hypogonadism [14]. Testicular imaging would be used in the
case of primary hypogonadism [14].
The primary symptom is a very low concentration of free
serum testosterone which is shared among a myriad of dis-
eases, conditions, and psychosexual issues. Due to this mas-
sive overlap, physicians should take final consideration and
caution when finalizing a diagnosis of hypogonadism.
Diagnosis of hypogonadism requires measuring serum testos-
terone levels, sperm count, FSH concentration, and LH con-
centration of the patient in question [3,7,8,15]. During sperm
analysis, motility of the sample is also taken into consideration
as an appropriate percentage of the sperm should be motile
[16,17].
The serum testosterone level takes precedence over the
other tests since low levels of testosterone is defining of
hypogonadism. Normal levels of testosterone in adult males
range between 300 and 800 ng/dL. A value less than 300 ng/
dL is an initial indicator for hypogonadism [3,7,8]. The
serum testosterone should be taken between 8:00 a.m. and
10:00 a.m. since testosterone levels fluctuate throughout the
day, with the highest testosterone production occurring in the
early morning. The volume extracted should be approximately
70% of total testosterone volume available [3,7,8].
Abnormities regarding SHBG may void the value of an eval-
uation of a serum testosterone evaluations since more pro-
duced testosterone will be left in its unbound form. In a sce-
nario where a patient is presumed to have hypogonadism
while experiencing a malfunction with their SHBG, free se-
rum testosterone level should be measured and compared to
their serum testosterone level [10,14].
Physiology and genetics of aromatase
The enzyme aromatase, through a series of biochemical pro-
cesses, converts free testosterone into 17 β-estradiol (E2) and
androstenedione into estrone when these substrates bind to its
heme cavity [1,20–22]. This enzyme is typically found in the
cytoplasm or the endoplasmic reticulum where it is regulated
by tissue specific promoters. [1,20,21] The regulation of
aromatase involves tissue-specific promoters which are regu-
lated by cytokines, hormones, and other external factors. In
males, aromatase resides in various tissues such as in the
brain, adipose tissue, gonads, blood vessels, skin, placenta,
and bone [1,20–22]. Extraglandular aromatization results as
the major source of estrogens within male; for this reason,
aromatase activity dictates endocrine, autocrine, and paracrine
effects on certain tissues targeted by estrogens [22].
Table 2 Etiology of primary or secondary hypogonadism
Primary hypogonadism Secondary hypogonadism
Klinefelter syndrome [24,25] Pituitary bleeding [26,25]
Chemotherapy [24,25] Kallmann’ssyndrome[26,25]
Radiation [24,25] Anorexia nervosa [26,25]
Myotonic dystrophy [24]
Cryptorchidism [26]Aging[26,25]
Hemochromatosis [24] Hyperprolactinemia [26,25]
Mumps orchitis [24] Prader Willi Syndrome [26,25]
Chronic opiate use [26,25]
Varicocele [26,25]
Infections [26,25] Benign tumors and cysts [27]
Malignant tumors [27]
Ketoconazole [26,25] Glucorticoid treatment [27]
Gonadal steroids [27]
GnRH analogs [27]
Tes tic ular t e ns i on [26,25] Morbid obesity [27]
Autoimmune damage [24]
Alkylating agents [26,25]
Glucorticoid [26,25]
Table 3 Conditions
associated with
hypogonadism
Sleep apnea [28]
Diabetes mellitus [29,30]
Anorexia nervosa [31,32]
Continuous opiate administration [33,34]
Excessive alcohol consumption [35,36]
SN Compr. Clin. Med.

The aromatase enzyme is a component of the cytochrome
P450 system, the system that regulates the conversion of es-
trogens from androgen precursors, and is encoded by the
CYP19A1 gene located on chromosome 15q21.2 [22]. This
gene has a coding region of 30 kilobases (kb), a regulatory
region estimated to be at least 93 kb, ten coding exons (II-X),
and upstream 5′noncoding exons, also known as exon Is [21,
23]. Tissue-specific regulation is possible due to the exon Is
each having an exclusive upstream promoter sequence re-
sponsible for alternative tissue-specific activity [21].
Examples of tissue-specific regulation can be examined with
the expression of promoter PII uniquely found in the gonads
[38]. Exon f is expressed in the brain while exon I.4 is
expressed in adipose tissue. Both of these exons are found
upstream of PII [38].
In the literature, eight males with aromatase deficiency
have been reported that had deficient levels of estradiol.
[28–31,39–42]. An unfused epiphysis leading to linear
growth into adulthood, a low bone mass, and above-
average body length was shown by these men. Testicular
size in these men ran from microorchidism to
macroorchidism and the plasma testosterone levels differed
generally in accordance with testis size. Levels of luteiniz-
ing hormone (LH) were either elevated or normal. Once
treated with estradiol, disturbances in the lipid profile im-
proved in most of these patients, BMD increased, and
epiphyses closed.
On the other hand, instances of aromatase excess regarding
familial cases have been reported. Aromatase excess syndrome
(AEXS), formerly known as familial gynecomastia, is a rare
genetic disease characterized by the pre-or peripubertal onset of
gynecomastia. As a result of overexpression of aromatase, in-
dividuals with AEXS experience symptoms associated with
hyperestrogenemia due to the increased conversion of andro-
gens into estrogens. Other symptoms include heterosexual pre-
cocity, prepubertal gynecomastia, hypogonadism, micropenis,
advanced bone maturation, and short final stature. The cause of
this disease has been hypothesized to be an inheritable autoso-
mal dominant genetic mutation of CYP19A1. A theme of pre-
mature bone maturation and gynecomastia are associated with
high peripheral estrogen synthesis. Stratakis et al. described a
situation in which an abnormal high expression of an alterna-
tive first exon was caused by aromatase excess sydnrome [32].
In addition, Shozu et al. described a situation in which the
aromatase gene was placed adjacent to cryptic promoter in a
case caused by chromosomal rearrangement [33].
These case reports delineate the vital commitment of estro-
gens to male wellbeing and distinguish the conceivable signs
and dangers of aromatase-inhibitor treatment in men.
Gynecomastia can be prevented by using an aromatase inhib-
itor. They might be utilized to expand gonadotropin discharge
and along these lines empower Leydig and Sertoli cell func-
tion. Aromatase inhibitors might be utilized to defer or avoid
epiphysial closure and thereby increase adult height. A note-
worthy concern of aromatase inhibition is the possible detri-
mental effect on bone mineralization [34].
Obesity and aromatase function
regarding hypogonadism
Obesity has become a prevalent problem for the overall health
of men in the modern world. An inverse relationship exists
between obesity and testosterone levels leading to a plethora
of sexual issues. Many studies confirm that increased obesity
in males increases the risk of hypogonadism [35,36,43–45].
However, the exact mechanism behind this association is still
under considerable consideration. Excess aromatase function
may be the cause of this relationship as a result of low testos-
terone levels left from the increased rate of conversion into
estradiol. These varied levels of estradiol and testosterone alter
fat distribution, adipocyte differentiation, and proliferation.
Adipose tissue primarily serves to store triglycerides.
However, this tissue has been observed to influence the
hypothalamic-pituitary-gonadal axis through its ability to se-
crete several hormones into the body via the bloodstream.
Mammals exhibit two types of adipose tissue: white adi-
pose tissue (WAT) and brown adipose tissue (BAT). Brown
adipose tissue stores triglyceride to convert to heat energy for
thermogenesis. This physiological function of fat to heat con-
version occurs in times where energy expenditure is needed
when experiencing situations where food is scarce and pre-
dominantly in situations where heat must be generated in or-
der to combat cold. White adipose tissue is responsible for the
energy storage in the form of triglycerides. Lipases convert
these triglycerides into fatty acids and glycerol. In situations of
energy depletion, lipolysis will release the fatty acids stored in
white adipose tissue into the plasma to catalyze energy
generation.
Obese males exhibit a high level of white adipose tissue.
Another character of white adipose tissue is the secretion of
adipose-derived hormones, adipokines, and increased aroma-
tase activity. The excess aromatase increases the rate of con-
version of androgens into estrogens such a testosterone into
estradiol. Obese males may be left with low physiological
levels of testosterone. Elevated levels of estradiol are hypoth-
esized to interact with the negative feedback loop of the
hypothalamic-pituitary-gonadal axis. With increased estradi-
ol, being an indicator of excess testosterone, LH secretion
would decrease causing an overall decrease in testosterone
production [37]. Support for this hypothesis is seen with the
use of aromatase inhibitors restoring testosterone, LH, FSH,
and serum estradiol to normal physiological levels [46]. This
mechanism proposes that excessive aromatase activity within
obese males causing a testosterone-estradiol shunt would lead
to hypogonadotropic hypogonadism (secondary
hypogonadism).
SN Compr. Clin. Med.

The contribution of leptin has also been noted to the man-
ifestation of hypogonadism within obese males. Leptin, a
pleiotropic cytokine-like hormone, has been found to have a
positive relationship with adiposity [47]. Excess leptin has
been observed to cause oxidative damage to the Leydig cells
themselves resulting in a disruption of steroidogenesis, which
would be a cause of primary hypogonadism [48]. Besides the
oxidative damage to the Leydig cells, the testosterone-
estradiol shunt (due to excess aromatase activity) is a major
contributor to obesity-induced hypogonadism.
Physiological low testosterone levels have been noted to
cause the accumulation of adipose tissue [8]. As mentioned
before, symptoms of hypogonadism include a decrease in
muscle mass, decrease in bone mineral density, and an accu-
mulation of fat. Other symptoms of hypogonadism that relate
to obesity include insulin resistance and an excessive lipopro-
tein lipase activity. Obesity-induced hypogonadism may trig-
ger a problematic cycle where obesity reinforces an individ-
ual’s hypogonadism while their hypogonadism will reinforce
their obesity.
Management
Aromatase inhibitors
Aromatase inhibitors are classified as first, second, or third
generation or as either nonsteroidal or steroidal [105].
Aromatase activity is inhibited by steroidal inhibitors such
as formestane and exemestane by resembling the substrate
androstenedione [106]. Nonsteroidal enzyme inhibitors
(anastrozole and letrozole) restrict enzyme activity by binding
with the heme iron of the enzyme [107]. First-generation aro-
matase inhibitors are considered to be nonspecific and weak.
They require adrenal supplementation as they can block other
steroidogenic enzymes. Third-generation inhibitors do not
hinder related enzymes and are potent.
Use of aromatase inhibitors can ease gynecomastia within
6 months and are possibly useful to prevent recurrence of
gynecomastia after reduction mastoplasty. It also promotes
virilization and increased testicular volume [49–51].
Aromatase inhibitors joined with agonists of
gonadotrophin-releasing hormone was sufficient for the pre-
vention of premature epiphysial closure in young men with
pubertas praecox of different etiologies [34]. Aromatase in-
hibitors can be used in boys who are short in height and those
who have a delay of puberty in order to increase adult height.
Aromatase inhibitors do not work well for the treatment of
gynecomastia in pubertal boys. They also have limited use
for the prevention of gynecomastia in bicalutamide-treated
men with prostate cancer. There is no consistent evidence
for a beneficial effect on spermatogenesis even though aroma-
tase inhibitors increase FSH levels [34]. Aromatase inhibitors
may come as an alternative for traditional testosterone
supplementation to improve testosterone levels for older
men with late-onset hypogonadism. It still remains controver-
sial of higher testosterone levels in older men and its long-
term benefits associate with it. Also, it is still uncertain if the
amount of testosterone can be stimulated by aromatase inhib-
itors for men who had low levels of testosterone [34].
Although selective aromatase inhibitors are relatively safe,
symptoms, such as bone fracture and arthralgia, have been
reported following long-term use in women with breast cancer
[52]. Through sex steroid therapy, male and female bone may
respond differently. It is unpredictable whether side effects
that occur in females also affect males with testosterone levels
elevated by the use of aromatase inhibitors [21]. No detrimen-
tal effects on bone metabolism have yet been reported in males
due to long-term use of aromatase inhibitors [53]. Side effects
of aromatase inhibitor use in men have not however been
determined [54].
Other treatment modalities for obesity-induced
hypogonadism
For all hypogonadal men, replacement of testosterone is indi-
cated except in patients where fertility is desired or when there
are contraindications. The goal of testosterone therapy is to
succeed in the development of secondary sexual characteris-
tics as well as help trigger puberty. It is also intended to raise
average serum testosterone levels into the mid-normal range
which is around 400–700 ng/dl. When testosterone levels are
back to the normal range in younger hypogonadal men, it
allows for an improved sexual function such as erectile func-
tion and libido. There is a controversy regarding whether tes-
tosterone has the ability to improve ED without the effects on
libido [55–60]. There is an increase in bone mineral density in
younger and older men with hypogonadal as an effect of tes-
tosterone replacement therapy [61–69]. It was recently found
that there is a decrease in waist circumference and body
weight in long-term testosterone replacement therapy [70,
71]. While the significant weight loss requires careful confir-
mation, randomized controlled trials showed that testosterone
replacement therapy reduced body fat mass, regional fat dis-
tribution, and waist circumference in hypogonadal men with
and without obesity [72–81]. Individuals with hypogonadism
and metabolic syndrome or type 2 diabetes have reported
slight improvements in insulin sensitivity, hemoglobin A1C
as well as a decrease in central adiposity [35,77,78,81–86].
The development of increased oiliness of skin and acne are
common adverse events of testosterone replacement therapy
because of the androgenic effects on the sebaceous gland [5].
Several major harmful effects are an increase in hemoglobin,
hematocrit, and red cell indices [87]. An increased risk of
cardiovascular events in older men showed to be more prev-
alent in a recent meta-analysis with testosterone treatment.
The increase cardiovascular event risks were higher in non-
SN Compr. Clin. Med.

pharmaceutical-supported compared to industry-supported
studies [88]. There was no increase in prostate cancer or pros-
tatic hyperplasia in the meta-analysis of placebo-controlled
clinical trials [87] Testosterone replacement in hypogonadal
men does not increase the risk of voiding symptoms of benign
prostatic hyperplasia [89] but may increase prostate size to
that of eugonadal men [90].
Impact of weight loss and loss of abdominal fat
on testosterone
Weight loss is related to testosterone therapy, and obesity is
related to reduced testosterone levels. Some mechanisms for
low testosterone in obesity complex mechanisms are in-
creased levels of sex hormone-binding globulin, androgen re-
sistance, insulin resistance, and low levels of luteinizing hor-
mone. The number of adipocytes and visceral fat is enhanced
with the loss of androgen receptor function. The normalization
of physiological testosterone levels reduces the activity of
lipoprotein lipase and triglycerides [95].
Complication of androgen replacement on prostate (BPH)
Currently, there has been no review or study that shows the
risk of prostate cancer associated with men undergoing testos-
terone replacement therapy. This is a question that has yet to
be answered. In a study with men who have prostatic
intraepithelial neoplasia (PIN) did not show an increased risk
of prostate cancer even though they are at a high risk for
prostate cancer [87]. An explanation that testosterone pro-
duces effects that do not alter intraprostatic androgen levels.
This was seen through a study by Marks et al., a double-blind
study that involved men with hypogonadism who were given
testosterone every 2 weeks for 6 months [100, ]. The results
showed that the levels of DHT and testosterone increased in
the serum, but no change in the hormones by prostate biopsy.
ED androgen replacement does not worsen urinary retention
and lower urinary tract symptoms (LUTS). However, prostate
size is shown to increase by 12 percent in accordance with
testosterone supplementation [101]. In some studies, the use
of androgen replacement has shown an improvement in
LUTS. In a randomized controlled trial conducted by
Shigehara et al., fifty two men were assigned to recieve an-
drogen replacement therapy [103,102]. Only twenty three
men had improvements with maximal urinary flow rates as
well as IPSS compared with controls. It is important to note
that the increase in prostatic hypertrophy in elderly men not on
androgen replacement therapy dos not differ with the increase
in prostate size of men on androgen replacement therapy.
Altogether, men diagnosed with benign prostatic hyperplasia
is not contraindicated with androgen replacement and and
does not drastically worsen LUTS [86].
Adverse effects of androgen replacement therapy
There are generally few if any side effects when restoring
testosterone back to physiological levels. In boys around pu-
berty, the increased testosterone levels stimulate erythropoie-
sis so there are higher hemoglobin levels in adult males com-
pared to females [91]. Therefore, it is suggested that the de-
crease in hemoglobin is secondary to the declining levels of
testosterone. Testosterone replacement is used for
hypogonadal men with anemia [91]. It is essential that the
hemoglobin levels be brought back to normal levels but not
past physiological range which may lead to a blood viscosity
that could cause thrombosis [91].The Endocrine Society rec-
ommends for men who have a baseline hematocrit below 50
should not be administered testosterone replacement in worry
of erythropoiesis. It is seen that the occurrence of erythropoi-
esis is related with the dosage of testosterone administered
[91]. A double-blind study demonstrated that using IM testos-
terone may influence thromboxane A2 (TXA2) which is a
platelet pro-aggregatory agent as well as a vasoconstrictor.
This may contribute to RBC adhesion of androgenic steroids
and thrombogenicity. It is to be noted that the patients were not
testosterone deficient all the way to baseline and the sample
size was small. [91]
Addiction to anabolic steroids
Anabolic androgenic steroids are pharmacological and chem-
ical derivatives of testosterone. The active molecules are 5 a-
dihydrotestosterone (DHT) and testosterone which are char-
acterized by 3-oxo groups and 17-B hydroxyl groups [92].
There is a nuclear receptor superfamily that the activity of
androgens is mediated by. The receptor is characterized by
two transcriptional domains AF-1 and AF-2 and a DNA bind-
ing domain. The hormone binds to the receptor ligand-binding
domain after it reaches the target cells. The receptor becomes
active when it is dissociated from protein chaperones where it
translates from the cytoplasm to the nucleus. The androgen
response element on the chromatin interacts with the activated
receptors and triggers the formation of a transcriptional com-
plex [92]. For nuclear-receptor-mediated transcriptional regu-
lation, co-activator and co-repressor complexes are in cells
which promote translation, gene activation, transcription,
and an alteration in cell function. Since the androgens are
steroid hormones, they are transported around in the circula-
tion by binding to plasma proteins [92]. A transport portion
that has high affinity for testosterone is SHBG which binds
around 60% of hormones transported in the blood. Albumin
has a high plasma concentration and is important for steroid
hormone metabolism [92].
There have been chemical modifications done to testoster-
one. For example, stanozolol was synthesized from
oxymetholone. Its purpose is for doping since it has anabolic
SN Compr. Clin. Med.

properties. Nadrolone is a hormone produced in females dur-
ing pregnancy in small quantities. It resembles the metabolism
of testosterone. When the methyl group to the carbon atom at
position 19 is substituted with a hydrogen atom, the ratio of
the anabolic and androgenic activities change [92].
Many people who are addicted to anabolic steroids and
those who abuse them will often use them in cycles. They
try to avoid the negative side effects from the drugs by going
on and off from them. The body becomes physically depen-
dent on the drugs when taken in a 6–12-week cycle [93].
When a user decides to take a withdrawal period, hormonal
imbalances caused by steroids make it dangerous for the user.
The symptoms are a psychological withdrawal as well as
headaches and muscles cramps (physical withdrawal symp-
toms). In a study conducted with 49 males, the common with-
drawal symptoms experienced were fatigue, depressed mood,
restlessness, anorexia, decreased libido, and insomnia [94].
Prostatic hyperplasia It is believed that young hypogonadal
males treated with testosterone leads to a significant growth of
the prostate. This was reported in men who had primary
hypogonadism. In a study, 13 men with Klinefelter's
sydnrome who were between the ages 25 and 32 years old
were administered intramuscular testosterone found an in-
creased size of the prostate [96]. In the majority of studies,
however, the effect of exogenous androgens on prostate-
specific antigen or prostate volume showed no effect for older
hypogonadal men [96]. Forty-four late-onset hypogonadal
men in a randomized controlled trial had found that those
treated with testosterone replacement therapy had no increase
in prostate tissue levels of DHT or testosterone even though
there were increased levels of serum testosterone. From the
years 1941 to 2008, Morgentaler and Traish had a theory
called the “saturation model”to demonstrate that the lack of
influence that testosterone replacement therapy has on pros-
tate volume or prostate-specific antigen in these men [96].
They believed that androgen concentration is not affected by
theprostateatnormallevelsoreveninmildhypogonadism
since the AR is saturated by androgens; this would then mean
that the maximum androgen-AR binding has been reached.
On the other hand, testosterone does become sensitive chang-
ing levels of androgen and low amount of testosterone.
Another concept is the development of benign prostatic hy-
perplasia in older men does not rely on testosterone but the
aromatization of androgens to estrogens. It then binds to es-
trogen receptors in the prostate and bladder [96] This concept
was evident in a study conducted by Schatzl et al. with men
over the age of 40 which showed that the increasing prostate
volume correlated with increasing estrogen levels and increas-
ing serum testosterone did not [102,96].
Cardiovascular disease There have been recent studies that
show a correlation with exogenous testosterone use with
adverse cardiovascular outcomes, but there is also an equal
amount of studies that demonstrate the exact opposite.
Therefore, at present, this issue remains controversial. Some
of the reasons why this may be being that there are differences
in trials with inclusion and exclusion criteria [97]. For in-
stance, age, underlying cardiovascular risk factors, degree of
clinical hypogonadism, baseline T levels, and patient mobility
[97].
It was previously believed that androgens could have an
atherogenic effect since as men aged, there was also an in-
creased incidence of cardiovascular disease (CVD) than com-
pared to aging women. Through androgen administration,
there could be an even higher risk of CVD since aging men
had already higher levels of testosterone. Recently, several
studies have found that testosterone replacement therapy
may have beneficial or neutral effects on cardiovascular risk
factors and complications. Meta-analyses that have been pub-
lished between 2005 and 2010 have shown that with testos-
terone replacement therapy (TRT) had no impact on the major
cardiovascular events but it did increase hemoglobin as well
as hematocrit [97]. Testosterone replacement therapy does
have a risk of leading to edema and water retention. There
still needs to be longitudinal studies that will help us under-
stand coronary artery changes and the effects of testosterone
replacement therapy.
Erythrocytosis Erythrocytosis is a condition where there is an
increased amount of red blood cells. These cells carry oxygen
from the lungs to tissues and organs. Erythrocytosis may be
primary or secondary. Primary erythrocytosis is due to an
alteration of hematopoietic progenitor cells, and secondary
erythrocytosis is signaling that is inappropriate (PDF). In older
men, erythrocytosis is very common. Compared to topical
preparations, the injection of testosterone replacement therapy
has a higher potential for erythrocytosis. Both hemoglobin
and hematocrit increase in a linear manner. Even though this
might be helpful for patients who have anemia, the long-term
effects are still unknown. According to epidemiological stud-
ies, as the levels of hematocrit increase, the higher the risk of
mortality and developing cerebrovascular disease. The mech-
anism for the effect of erythropoiesis on testosterone is still not
known. There is controversy on the administration of testos-
terone replacement therapy since itis believed to havea risk of
potential venous thromboembolism (VTE) [98]. It was pro-
posed that due to the secondary blood profile changes, this
would cause risk for VTE; however, VTE not correlating with
polycythemia and erythrocytosis has doubted this notion [98].
Because the risks that are associated with testosterone replace-
ment therapy are still not known, it is crucial to take notice of
the elevated levels of Hb and Hct.
A recent study conducted by Bachman et al. may provide
an idea of what the mechanism should be. It was hypothesized
that there was a multicomponent system to explain the effects
SN Compr. Clin. Med.

of testosterone replacement therapy [98]. The results indicated
that serum EPO levels had significantly increased from base-
line into the normal range just after 1 month for the TRT group
compared to the control group [98]. The erythropoietin (EPO)
levels stayed at constant elevated levels post-HB increase
which meant that there was not a negative feedback inhibition.
While, the Hb-EPO set point was altered for the TRT group as
opposed to the control group [98]. During TRT, the levels of
iron metabolism were also altered. Hepcidin, which regulates
the entry of iron in the circulation of mammals, was found to
be decreased by 49% in the TRT group. Conversely, iron-
turnover increased which served as a sign of iron-dependent
erythropoietitic activity. This lead to increases in Hb and Hct
based on the four components [98]. The conclusion that
Calado et al. had arrived from these results showed that there
would be an increase in transcription based on the influence of
estradiol; the estrogen receptor alpha binds to a promotor that
is located on the telomerase reverse transcriptase gene. The
increased transcription would increase telomerase stability,
which would increase hematopoietic stem cell proliferation.
There still needs to be larger studies to understand Hb and Hct
as side effects of testosterone replacement therapy since the
risk of vascular disease is still unclear [98].
Reduced aromatase levels in hypogondal diabetic men and
estrogen and androgen receptors Ghanim et al. observed that
in hypogonadal men with type 2 diabetes, the expression of
ERalpha and AR receptors in adipose tissue were much lower.
Therefore, this indicates that there is a deficiency in mecha-
nisms converting testosterone to aromatase and the ones asso-
ciated with the estradiol response in ER [99]. There is an
intensification of the defect rather than a compensatory re-
sponse to testosterone deficiency. Testosterone replacement
causes an increase in the expression of aromatase, AR, and
ERalpha, since it leads to an increase in estradiol and plasma
testosterone concentrations. There was also an increase in nu-
clear protein content of AR in MNCperipheral blood mono-
nuclear cells and expression of AR. The study conducted by
Ghanim et al. concluded that testosterone replacement re-
stored AR expression levels to the normal levels in eugondal
men [99]. The increase in improved insulin body mass during
hyperinsulinemic euglycemic clamp and lean body mass has
been caused through enhanced AR levels since the target of
testosterone action is skeletal muscle. Estradiol concentrations
are decreased due to low testosterone concentrations because
of a reduction in the testosterone required for the formation of
estradiol. The reduction of estradiol must indicate that there is
a dual mechanism. Obese eugondal men have higher estradiol
concentrations as compared to obese hypogonadal men.
Testosterone concentration in obese and lean men is not de-
finitive of the expression of aromatase in subcutaneous adi-
pose tissue. Furthermore, an impairment of estradiol action
will result due to the reduction in the expression of ERalpha.
Since the absence of aromatase is associated with osteoporosis
in men, it has been demonstrated that the bone density is
determined from estradiol concentrations [99].
Conclusion
Hypogonadism is common among the male population espe-
cially in older men who are obese. The role of aromatase is
often overlooked when examining an adult male for obesity-
associated hypogonadism. Lack of exercise can influence tes-
tosterone levels negatively. Low physiological testosterone
levels cause an accumulationof adipose tissue with symptoms
of a decrease in bone mineral density and accumulation of fat.
The use of testosterone replacement therapy can be addicting
and can cause the user to have bothphysiological and physical
withdrawals.
Acknowledgements The authors are thankful to Drs. Inefta Reid, Kelly
Warren, Todd Miller, and Peter Brink for departmental support, as well as
Mrs. Wendy Isser and Ms. Grace Garey for literature retrieval.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of
interest.
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