Corona Et Al., 2015 ING

Review
The pharmacotherapy of male

hypogonadism besides androgens
Giovanni Corona, Giulia Ratrelli & Mario Maggi†
†
1. Introduction University of Florence, Department of Experimental, Clinical and Biomedical Sciences, Sexual
Medicine and Andrology Unit, Florence, Italy
2. Testicular testosterone
formation Introduction: Adulthood male hypogonadism (HG) is the most common form
3. Hypogonadism: a testicular of HG. Although testosterone (T) replacement therapy (TRT) is the most com-
failure in testosterone mon way of treating HG, other options are available depending on patient’s
production needs and expectations.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Selcuk Universitesi on 01/20/15
4. Prevalence and main Areas covered: We analyze alternative options to TRT as a medical interven-
manifestations of HG tion in treating HG. Gonadotropin (Gn) therapy is the treatment of choice in
5. Treatment of HG
men with secondary HG (sHG), who require fertility. Gonadotropin-releasing
hormone therapy represents an alternative to Gn for inducing spermatogen-
6. Conclusion
esis in patients with sHG, however, its use is limited by the poor patient com-
7. Expert opinion pliance and high cost. In obese HG men, lifestyle modifications and, in
particular, weight loss should be the first step. Recent data suggest that anti-
estrogens represent a successful treatment for sHG. Other potential therapeu-
tic options include the stimulation of hypothalamic activity (i.e., kisspeptin
and neurokinin-B agonists). Conversely, the possibility of increasing Leydig
cell steroid production, independently from Gn stimulation, seems unreliable.
For personal use only.
Expert opinion: Understanding the nature of male HG and patient’s needs are
mandatory before choosing among treatment options. For primary HG only
TRT is advisable, whereas for the secondary form several alternative possibili-
ties can be offered.
Keywords: antiestrogens, gonadotropin, male hypogonadism, testosterone
Expert Opin. Pharmacother. (2015) 16(3):369-387
1. Introduction
The male gonad, the testis, is the unique site where male germ cells (sperm) are pro-
duced and grown. The vast majority of testicular space is dedicated to this mission,
with seminiferous tubules enriched in spermatogenic cells, at different stages of mat-
uration, and somatic cells (Sertoli cells) that support germinal cell growth and dif-
ferentiation. When Enrico Sertoli originally described the Sertoli cells, he used the
term ‘mother cells’, suggesting a unique role for these cells in germ cell maturation
and development [1]. Sertoli cells are also involved in hormonal activity, producing
several peptides, with both paracrine and endocrine functions, as is the case for the
inhibin-related peptides [2-4]. In a minority of specialized mesenchymal cells, located
in the interstitium between seminiferous tubules, there is the production of other
hormones, sex steroids, which, locally, favor spermatogenesis and, systemically, tar-
get several tissues, essentially turning phenotype and behavior from male into men.
These sex-steroid secreting specialized endocrine cells number ~ 500 million and
are termed Leydig cells, after the German anatomist Franz Leydig, who discovered
them in 1850 (see for review [2-4]).
In adult men, Leydig cells actively synthesize and release testosterone (T), the
major circulating androgen, with an estimated production rate of 5 -- 7 mg/day. In
target tissues, T itself, or its potent metabolite dihydrotestosterone (DHT, produced
after 5a-reduction), binds with high affinity (subnanomolar range) to the androgen
receptor (AR). In addition, T and its precursor, D4 androstenedione, can be actively
10.1517/14656566.2015.993607 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 369
All rights reserved: reproduction in whole or in part not permitted
G. Corona et al.
(sHG) in adults [6]. Neurokinin-B is co-expressed with

Article highlights. Kiss-1 and dynorphin-A by kisspeptin neurons in the hypo-
. Lifestyle modifications and weight loss should be the thalamus, that, for this reason, are named KNDY neurons [7].
first step in obese or overweight men with TACR3 is not expressed by GnRH neurons [7] but it is
hypogonadism (HG). by KNDY cells, so that neurokinin-B is hypothesized to act
. Restoring sexual activity might improve testosterone
in an autocrine or paracrine manner to enhance secretion
levels in mild form of HG.
. Gonadotropin therapy is the treatment of choice in men of Kiss-1, thus indirectly affecting GnRH-Gn secretion
with secondary HG who require fertility. (Figure 1) [7]. Leptin, the major adipokine produced by fat
. Antiestrogens might represent a successful treatment for stores, also facilitates puberty onset, by activating Kiss-1 sig-
some forms of secondary HG. naling [5]. Leptin maintains its permissive role on overall
. Other potential options include: Stimulation of
reproductive activity throughout adulthood, however, a detri-
hypothalamic activity: kisspeptin and neurokinin-B
agonists.Stimulation of Leydig cell steroid production, mental effect of leptin excess has also been described [8].
independently from gonadotropin stimulation:
phosphodiesterase type 5 inhibitors. 2. Testicular testosterone formation
The binding of LH, or of its structurally related molecule,

transformed, through P450 aromatase, to other bioactive human chorionic gonadotropin (hCG), to their common
metabolites, such as estrone and 17-b-estradiol (E2) (daily receptor (LHCGR) -- a seven transmembrane, G-protein-
production about 45 µg), which activate estrogen receptors associated protein -- stimulates testicular steroidogenesis [9].
(ERa and ERb) [2-4]. A small amount of E2 can also be syn- Upon hormone binding, LHCGR receptor shifts conforma-
thesized within the testis and released in the peripheral tion and thus mechanically activates stimulatory G protein,
circulation [2-4]. In the adult male, sex steroids have numerous which detaches from the receptor and activates adenylyl
biological functions (Figure 1), essentially devoted to stimulat- cyclases (ACs), converting ATP into the second messenger,
ing/maintaining male characteristics and behaviors. They are cAMP. Thereafter, cAMP activates cAMP-dependent protein
essentially derived from the selective activation of the AR, by kinase (PKA), which, in turn, promotes T synthesis, through
T or DHT, or by the activation of ERa or ERb by E2, or a phosphorylation and activation of key enzymes involved in
combination thereof, as in the case of the central nervous sys- cholesterol handling and transport, such as the steroidogenic
tem (CNS), including hypothalamus and pituitary gland, or acute regulatory (StAR) protein, a rapidly synthesized labile
bone matter [2-4]. phosphoprotein, and the hormone-sensitive lipase (HSL)
Spermatogenesis is a highly complex process, involving (also known as cholesterol ester hydrolase). The transport of
subtle and continuous interactions between paracrine and auto- cholesterol from intracellular stores and from the outer to
crine regulators -- among which T is the most important -- and the inner mitochondrial membrane forms the first and rate-
the pituitary-derived gonadotropins (Gn): follicular-stimulat- limiting step in steroid hormone biosynthesis, allowing
ing hormone (FSH) and luteinizing hormone (LH), which CYP11A1 (cytochrome P450 side chain cleavage) to convert
mainly control seminiferous and Leydig cell activity, respec- it into steroid intermediates. In humans, StAR mutations
tively (Figure 1) [3,4]. cause lipoid congenital adrenal hyperplasia that ranges from
LH and FSH secretion from the anterior pituitary are finely an almost complete inability to synthesize steroids [10], to
regulated by inhibitory influences coming from the testis itself less severe forms that retain partial StAR protein activity [11].
(sex steroids and inhibin B) and stimulated by the secretion in The 18-kDa translocator protein (TSPO) [12], previously
the portal vessels of the pituitary stalk of the decapeptide, known as the peripheral-type benzodiazepine (BZD) receptor
gonadotropin-releasing hormone (GnRH), synthesized in the (PBR) -- a pharmacologically distinct and unrelated g-amino-
arcuate nucleus of the hypothalamus (Figure 1). The GnRH butyric acid (GABA)-associated BZD binding site [13] -- is also
pulsatile secretion is negatively controlled by the activity of expressed predominantly in mitochondria from steroid syn-
other hypothalamic neurons, including corticotrophin-releas- thesizing cells, where it is localized to the outer mitochondrial
ing hormone and b-endorphin neurons. Conversely, Kiss-1 membrane. TSPO binds to cholesterol with high affinity and
neurons, through the activation of the specific Kiss-1 receptor, is supposed to cooperate with StAR in transporting it from
G protein-coupled receptor-54 (GPR54; [3,5];), are the main the outer to the inner mitochondrial membrane, where cho-
components involved in the stimulation of GnRH secretion. lesterol is then converted into the first steroid, pregnenolone,
Infusion of Kiss-1 in humans stimulates GnRH secretion by CYP11A1, an enzyme located on the matrix side of the
from the hypothalamus, leading to an increase in LH and mitochondria. In addition, PKA activation also has a longer
FSH secretion and a corresponding rise in T (Figure 1). lasting influence on steroidogenesis. In the chronic phase of
Another peptide, neurokinin-B or TAC, is involved in steroid production, mRNA transcripts of several of the key
GnRH-Gn secretion acting through its receptor TACR3. steroidogenic genes increase due to cAMP/PKA-mediated
Inactivating mutation of its gene or that encoding activation of transcription factors, including shape factor-1
TACR3 cause delayed puberty or secondary hypogonadism (steroidogenic factor 1) and DAX-1 (dosage-sensitive sex
370 Expert Opin. Pharmacother. (2015) 16(3)

Alternative therapy for male HG
Arcuate nucleus
Hipothalamus
Neurokinin B
CHR neuron
GPR54 β endorphin neuron
TAC3R
Kisspeptin
GnRH neuron
KNDY neuron
GnRH
Pituitary
LH, FSH
Sex steroids
T,17βE2
Leptin
FSH
Seminiferous
tubules
LH
Adipose tissue Testis
Sex steroids
T,17βE2
Leydig island
Andrologic and estrogenic effect
External and internal

Skeleton Muscle Mood Erythrocytes Sperms Voice genitals Skin
AR, ERα, ERβ AR AR, ERα, ERβ AR AR AR AR AR
Figure 1. Schematic regulation of the hypothalamus--pituitary--testis axis and the testosterone (T) target tissues.
AR: Androgen receptor; CRH: Corticotrophin-releasing hormone; ER: Estrogen receptor; FSH: Follicular-stimulating hormone; GnRH: Gonadotropin-releasing
hormone; GPR54: Kiss-1 receptor; G protein-coupled receptor-54; LH: Luteinizing hormone.
reversal-adrenal hypoplasia congenita critical region on the X functional compartments. Beside cAMP, also cGMP might
chromosome gene 1) [14]. All of these regulatory processes are have a role in controlling T synthesis. Stimulation of cGMP-
controlled by cAMP, although possibly by different pools or dependent protein kinase G (PKG) production phosphorylates
Expert Opin. Pharmacother. (2015) 16(3) 371

G. Corona et al.
StAR protein in vitro and initiates steroidogenesis [15,16]. The dysfunction (ED), mood symptoms, low bone mineral den-
Leydig cells express several cGMP hydrolyzing phosphodiester- sity and mild anaemia, all of which can contribute to decreas-
ases (PDEs) including PDE type 5 (PDE5) [17], whose activity ing the overall quality of life [2]. However, it should be
might participate in regulating T synthesis. recognized that many of these symptoms are rather non-spe-
Within the testis, T concentrations are two log units cific, as they are also characteristic of the aging process per
higher than those in peripheral circulation, reaching micro- se, which, in turn, may act as a confounder in the interpreta-
molar levels. In a study, the mean concentration of T in testis tion and identification of the syndrome. Hence, according
aspirates obtained from the 21 patients was 609 ± 50 µg/l to major international guidelines, the diagnosis of adulthood
(almost 2 µM), that is, at least 200-fold greater than the con- HG (also known as late-onset HG [LOH]) should be made
centration of T found in normal human serum [18]. It has with two separate biochemical determinations of serum
been previously reported that in spermatic venous plasma T levels along with the presence of consistent symptoms and
the efferent level of T was 259 ± 133 µg/l, suggesting that signs [2]. Different T thresholds have been proposed for the
the majority of Leydig cell-produced T is exported towards biochemical definition of low T [2,25]. The most widely shared
the periphery [19]. Accordingly, intratesticular T concentra- consensus [2,25] is that T substitution has to be offered to
tions required for maintaining spermatogenesis is very low symptomatic individuals when circulating total T is below
(< 5% of the usual intratesticular T concentrations [20-24]). 8 nmol/l (231 ng/dl). In addition, there is also general agree-
Local actions of T, besides spermatogenesis, are still a matter ment that a total T level above 12 nmol/l (346 ng/dl) does not
of debate [2-4]. require substitution. When total T is repetitively > 8 and
< 12 nmol/l in the presence of typical hypogonadal symptoms
3. Hypogonadism: a testicular failure in (as listed before), a T treatment trial may be considered [2,25].
testosterone production Guidelines proposed by the American Association of Clinical
Endocrinologists [26] and by the Endocrine Society [27] differ
The inadequate gonadal production of T is known as HG, in the T-threshold suggested, considering a cutoff of
a common condition due to an intrinsic testicular failure 7 nmol/l (200 ng/dl) and 10.4 nmol/l (300 ng/dl), respec-
(primary HG) or to a suboptimal stimulation by pituitary tively. Recently, by evaluating data form the European Male
Gn (secondary or central HG). The term male HG, however, Ageing Study (EMAS), obtained from more than 3400 com-
in clinical practice, is rarely used to identify isolated abnormal- munity-dwelling middle-aged and older men (40 -- 80 years)
ities in sperm production and is more often applied to describe across 8 European centres, Wu et al. [28] introduced a new def-
any T (and spermatogenetic) deficiency. Both primary HG inition of LOH. In particular, they demonstrated a syndromic
and sHG, if not treated, are characterized by symptoms and association between decreased T levels (total T < 11 nmol/l)
signs of dramatically different severity, spanning from a com- and a triad of sexual symptoms: low libido, and reduced spon-
plete pseudo-female phenotype to no or very mild phenotype taneous and sex-related erections [28]. Therefore, according to
changes, dictated more by the age of onset of the testicular fail- EMAS criteria, LOH should be diagnosed in the presence of
ure than by the cause of this failure [2-4]. at least three sexual symptoms and a morning total T level
of less than 11 nmol/l (230 -- 319 ng/dl) and free testosterone
4. Prevalence and main manifestations of HG levels of less than 222.2 pmol/l (< 64 pg/ml).
By applying only biochemical criteria, the prevalence of
When HG develops during early fetal life, symptoms can be LOH has been reported to be up to 15% in the general pop-
very severe, ranging from an almost complete feminine body ulation [2]. However, by using the EMAS criteria, the preva-
shape (complete androgen insensitivity or enzymatic defects lence of LOH is much lower, that is, 2.1% [28]. It is quite
blocking androgen synthesis) to various defects in virilization evident, however, that subjects complaining of sexual dys-
such as in the case of impaired secretion or activity of GnRH function represent a population overloaded with LOH with
or Gns [2]. In the case of a peripubertal appearance of HG, prevalence five to six times higher than that reported in the
due to central (e.g., pituitary tumors, as germinoma) or general population [29].
peripheral defects (such as Klinefelter’s syndrome), there
might be a slowing down of or delay in puberty progression, 5. Treatment of HG
with a eunuchoidal phenotype. Hypogonadism onset in the
prepubertal period is rather uncommon although not so T deficiency can be successfully treated by supplying the defi-
rare, spanning from 1:100,000 for complete androgen insen- cient hormone, T, which is available in oral, transdermal and
sitivity syndrome to 1:500 for Klinefelter’s syndrome [2]. injectable formulations (reviewed in [29,30]). T replacement
Hypogonadism with a clinical exordium in young adulthood therapy (TRT) is considered the most common and simple
or later on due to any reason is the most common cause of way of treating HG. However, it has several limitations,
male HG. It includes relatively mild, insidious and difficult because turning off Gn production will suppress any residual
to recognize, but often bothersome and frustrating, symptoms testicular activity, including spermatogenesis. Hence, the par-
such as weakness and fatigue, reduced libido and erectile adoxical effect of treating male HG with exogenous T is that it

Table 1. Available preparations to treat male hypogonadism.
Compound Trade name Standard dosage Advantage Disadvantages
GPR54 agonist
TAK-448 Only Phase I data NA NA NA
TAK-683
TACR3 agonist
Senktide Only Phase I data NA NA NA
[MePhe7]NKB
Antiestrogens
Clomifene Clomid 25 -- 50 mg/day Useful in functional Limited risk of venous
Tamoxifen Nolvadex Istuba 100 -- 150 mg/week hypogonadotropic thromboembolic
Enclomiphene Valodex 12.5 -- 25 mg/day hypogonadism Required intact
Androxal Suggested in idiopathic hypothalamus--pituitary--testis
infertility axis
Gonadotropin available compounds
hCG Novarel 1000 -- 2000 IU Low cost Mixed combination with FSH
Extractive Chorex 3 times/week Efficacy in patients with
Gonic GnRH receptor mutations
Choron
Chorigon
Pregnyl
Gonasi
Prophasi
hCG Ovidrel 1000 -- 2000 IU No association with FSH High cost
Recombinant 3 times/week Efficacy in patients with Not proved advantages vs
GnRH receptor mutations extractive hCG
Luteotropic hormone Ovitrelle NA No combination with FSH High cost
Recombinant No data on infertile men

FSH Menogon 75 -- 150 IU 3 times/ Low cost Mixed association with hCG
Extractive Meropur week efficacy in patients with
GnRH receptor mutations
FSH Gonal F 75 -- 150 IU 3 times/ No combination with HCG High cost
Recombinant Puregon week Efficacy in patients with No advantages on extractive
GnRH receptor mutations FSH on infertile men
FSH: Follicle-stimulating hormone; hCG: Human chorionic gonadotropin; NA: Not available.
induces further testis atrophy and infertility, by inhibiting or neurokinin-B agonists that, theoretically, activate the entire
Gn secretion. GnRH-Gn-testis axis (Figure 1 and Table 1; see section 1&2
The aim of this review is to critically scrutinize alternative and [31] for review).
options to T as a medical intervention in treating HG. Both native and synthetic kisspeptin agonists have been
According to the physiology of hypothalamus--pituitary--testis studied. Native forms are peptides of 54 or 10 amino acids
axis, the goal can be reached by increasing: i) hypothalamic (kisspeptin-54 and -10, respectively the native 54 amino
(i.e., kisspeptin and neurokinin-B agonists) and/or ii) pituitary acid kisspeptin and the C-terminal decapeptide) both with
activity (i.e., GnRH analogs, antiestrogens), or by mimicking full biological activity, but low molecular stability. Synthetic
pituitary activity; (i.e., Gn), or, finally, iii) by increasing Ley- compounds are modifications of kisspeptin-10 made for pro-
dig cell steroid production, independently from Gn stimula- viding resistance to degradation and improving pharmacoki-
tion (i.e., PDE5 inhibitors, TSPO agonists). Obviously, netics. Examples of synthetic kisspeptin agonists are
removing the main cause of HG is the first step in a successful TAK-448 or TAK-683, currently investigational synthetic
management of T deficiency. Considering that a consistent peptides (nine amino acids), modified from kisspeptin-10,
fraction of adult-onset HG is associated with obesity and met- which bind to GPR54 with an affinity similar to that of native
abolic syndrome (MetS), the effect of medical treatment of peptides [32,33], thus stimulating GnRH release. The native
these conditions will be also considered. kisspeptin-54 and -10, acutely administered in healthy men,
have been proven to elicit a strong stimulation of Gn secre-
5.1Stimulation of GnRH secretion: kisspeptin tion [34,35], and a continuous infusion of kisspeptin-10 for
and neurokinin-B agonists 22.5 h produced an increased amplitude and pulse frequency
The most physiological approach to sHG therapy, but still of Gn secretion [35]. Either acute or continuous administra-
not available for clinical use, is based on the use of kisspeptin tion of kisspeptin-10 has also been tested in men with

G. Corona et al.
Type 2 diabetes mellitus (T2DM) and sHG [36] and it has The necessity of wearing a pump 24 h a day for a long time
proven to be able to restore T levels within the normal range. is the major inconvenience limiting the use of GnRH as a
TAK-448 and TAK-683 are characterized by a higher activity therapy for sHG [41]. In addition, the lack of sufficient infor-
and stability than the native peptides [37] and, therefore, they mation in improving LOH-related symptoms represents
are mainly studied for therapy of prostate cancer. In fact, another limitation.
when continuously infused in healthy men, they suppress
T levels into the castrated range [38,39]. Hence, a pulsatile 5.2.2 Antiestrogens
administration of these synthetic analogs could be theoreti- The classic, genomic effects of estrogens are mediated
cally offered as a new option for sHG. However, similar to through the transcriptional program of estrogen nuclear
what has been observed for GnRH therapy (see below), the receptors ERa and ERb. On these receptors, some estrogen
requirement of wearing portable pumps could limit kisspeptin antagonists, having a steroid backbone different from native
agonist use due to expected poor patient compliance and estrogen, can exert both antagonistic and agonistic effects in
high cost. different estrogen target tissues. Hence, a class of compounds
Few neurokinin-B agonists (Senktide and [MePhe7]NKB) also known as mixed partial ER agonists (Table 1) has been
have been developed for having a higher stability and affinity developed. The first non-steroidal partial ER agonist, etha-
for TACR3 than the native molecule [31]. Although they still moxytriphetol or MER-25, was synthesized more than
have not been tested in clinical studies, neurokinin-B agonists 50 years ago [47], but never developed clinically because of
could be potentially new therapeutic options for treatment of high toxicity and low potency. The triphenylethylene deriva-
sHG. However, no clinical studies are at present available on tive compound, MRL-41, now known as clomiphene citrate,
neurokinin-B agonists and stimulation of Gn secretion. was developed in 1961 and is made of enclomiphene (trans-
isomer, 62%) and zuclomiphene (cis-isomer [43]). The former
5.2 Stimulation of pituitary activity shows only antagonistic activity, while the latter has mixed
5.2.1 GnRH therapy properties and longer half-life: 30 days versus 10.5 h [48].
GnRH therapy can be used, alternatively to T, in starting There are currently two main chemical classes of mixed par-
puberty and testicular growth, but they can also induce sper- tial ER agonists approved for clinical use in females: the
matogenesis in patients with sHG. GnRH, when adminis- first-generation triphenylethylene derivatives (clomiphene,
tered in a pulsatile manner, physiologically stimulates tamoxifen and toremifene), which are used for female infer-
pituitary to release LH and FSH. This limits its use to subjects tility and in the treatment and secondary prevention of breast
with a residual pituitary gonadotropic activity and it cannot cancer, and raloxifene, a second-generation benzothiopene
be a therapeutic option in sHG due to mutation in GnRH derivative indicated for the treatment and prevention of oste-
receptor. GnRH therapy for treatment of sHG must be oporosis. Bazedoxifene acetate is a new, third-generation,
administered in a pulsatile fashion, mimicking the activity mixed partial ER agonist. Other classes include benzopyrans
of hypothalamic pulse generator [40,41]. and naphthalenes (e.g., lasofoxifene).
At the moment, GnRH therapy represents the most phys- Tamoxifen shows an agonistic effect on another class of
iological, orthotropic approach for GnRH deficiency, iso- ER: the orphan receptor G protein-coupled receptor 30 or
lated or in combination with other hypothalamic hormone G protein-coupled ER (GPR30/GPER) [49]. GPR30/GPER
deficiencies. Dosage required for stimulating a pulsatile secre- is localized in the cell membrane, as well as in intracellular
tion of Gn is the intravenous or subcutaneous administration membranes, and is widely expressed in the genitourinary tract,
of 100 -- 400 ng/kg of GnRH every 90 -- 120 min and titra- including testis, corpora cavernosa, prostate and bladder [50].
tion must be performed on the basis of T, LH and FSH lev- We recently demonstrated that, in corpora cavernosa [51]
els [41]. A meta-analysis of the available longitudinal studies and prostate, tamoxifen behaves as an ERa antagonist,
dealing with appearance of sperm in semen of azoospermic whereas in the prostate it acts as a GPR30/GPER agonist [50].
sHG subjects upon pulsatile GnRH [40] showed that sper- In the male, all mixed partial ER agonists show a rather
matogenesis is achieved in 75% of cases with a mean sperm similar biological profile, although with some differences
count of about 4 million/ml. Studies comparing spermato- related to the different characteristics of the compound
genesis obtained with GnRH or Gn therapy substantially (Table 1). Essentially, all show an antagonistic activity versus
report a non-significant difference between these two thera- ERs in the hypothalamus--pituitary centres, regulating Gn
peutic approaches [42-45]. Effectiveness of GnRH in improv- release. In fact, all mixed partial ER agonists increase LH
ing sexuality has been mainly studied in prepubertal-onset and FSH secretion in the bloodstream and therefore stimulate
sHG subjects, as a part of the clinical picture of pubertal testis activity both in terms of spermatogenesis and steroido-
development. Few studies also evaluated its effect in improv- genesis. However, due to an agonist activity in the liver they
ing sexuality in non-HG men, without finding substantial also increase sex hormone binding globulin (SHBG), there-
success [46]. However, no study has systematically evaluated fore, the resulting fraction of unbound (free) T is often
GnRH therapy in improving sexual and other HG-related unchanged [49,52-55]. Another, unwanted, agonist effect of
symptoms in adult men with LOH. mixed partial ER agonists is venous thromboembolic disease,

although the absolute risk is relatively small [49,56,57]. Concern- including clomiphene, on pregnancy rate [77,78]. In contrast, a
ing other mixed partial ER agonists’ activity in the male, more recent meta-analysis of randomized controlled trials
tamoxifen has been shown to maintain some estrogenic action (RCTs) on antiestrogen as an empiric medical therapy for
in genital tissues such as the epididymis [58] and bone. In fact, male infertility indicates that they can improve spontaneous
following administration of other mixed partial ER agonists, pregnancy rate, sperm concentration and motility [79]. Use
such as raloxifene and toremifene, an increased bone mineral of clomiphene for increasing sperm retrieval from ejaculate
density has been demonstrated in men treated with GnRH or testicular biopsies in otherwise azoospermic subjects was
agonist, and therefore hypogonadal [59]. In this patient pop- suggested [80]. Tamoxifen citrate was introduced three decades
ulation, toremifene (80 mg/day) demonstrated, in a large, ago as an empiric treatment for idiopathic oligospermia [81].
placebo-controlled Phase III study, not only to prevent bone Tamoxifen, in subjects with infertility, was also able to
loss, but also to decrease the risk of fracture [56,57]. In addition, increase T and Gn [82,83] and similar results were also reported
in prostate cancer subjects undergoing androgen-deprivation in a small sample of healthy subjects [84,85]. Accordingly, the
therapy (ADT) with bicalutamide, tamoxifen administration aforementioned Chou meta-analysis showed a significant pos-
(20 mg) was able to significantly ameliorate gynecomastia itive effect of antiestrogens on FSH and T levels [80].
and mastalgia [54,60-62]. Hence, the possible use of mixed partial Enclomiphene (Androxal), the trans-isomer of clomiphene
ER agonists in prostate carcinoma patients undergoing ADT is citrate (see before), is being developed by Repros Therapeutics
emerging for treating gynecomastia and preventing bone loss. Inc., The Woodlands, TX, USA, for promoting Gn-dependent
Similarly, this class of drugs can be combined with T for the T secretion in sHG. Enclomiphene was first tested in a
treatment of TRT-induced gynecomastia [4]. Phase IIb, randomized, open-label, fixed-dose (25 mg) clinical
Only a limited number of studies are available on mixed trial in 12 men with obesity (mean weight = 105 kg) and sHG
partial ER agonists in treating male HG (Table 2). Shabsigh (total T < 10.4 nmol/l), previously treated with T gel. The pri-
et al. [63]. reported positive results in terms of T rise with clo- mary end point was change in hormonal and seminal profile
miphene citrate (25 mg/day) in a study on 36 men with from baseline and comparison with results obtained during
T deficiency (<10.4 nmol/l), thus confirming the previous T transdermal application. Results indicated a similar rise in
experiences of Guay et al. [64,65]. in subjects with ED. total T for gel and enclomiphene, the latter being able to
Katz et al. [66]. confirmed these positive results in a prospective increase LH and FSH concentration and sperm count [86].
series of 86 men with low-normal LH (< 6 mU/l) and low No significant change was noticed in SHBG and calculated
T (< 10.4 nmol/l) treated with 25 -- 50 mg/day of clomiphene free T [86]. In another single-blind, 6-week, randomized Phase
for a mean duration of almost 20 months. They observed a II study, the effect of increasing concentrations of enclomi-
more than twofold rise in circulating T and LH, along with phene (6.25, 12.5, 25 mg) was tested and compared with
improvements in several HG-related symptoms, including T gel (50 mg/day) in 44 subjects with obesity (mean body
lack of libido. Another recent study indicates that clomiphene mass index [BMI] = 34.7 kg/m2) and sHG (total T <
is able to restore normal T and LH levels and to improve 12 nmol/l and LH < 12 intrauterine [IU]/l) with primary
sperm motility and erectile function in most (70%) male end point variation in total T and LH [87]. A pharmacokinetic
patients with prolactinomas and persistent HG under usual study of different doses of enclomiphene was also performed.
dopaminergic therapy [67]. The same group, however, in an With enclomiphene citrate, there was a significant increase in
open-label, single-arm study of nine hypogonadal subjects total T level, which, at the maximal dose, was comparable
with non-functioning pituitary adenomas, failed to demon- with T gel. However, in the enclomiphene arms, LH was
strate any advantage of clomiphene citrate (50 mg/day) [68]. dose-dependently stimulated, whereas it was suppressed in
Hence, an intact hypothalamus--pituitary axis is required for the T transdermal arm. The positive effect of enclomiphene
the successful outcome of antiestrogens in increasing on LH and T persisted 1 week after discontinuation of the
T levels. Since an increased estrogen-mediated negative feed- drug. In this, as in the previous study, an enclomiphene-
back on hypothalamus--pituitary gland has been hypothesized associated IGF-1 decline was noted. The authors recognized
as a possible cause of obesity-induced T deficiency, it is con- that the highest doses (12.5 and 25 mg) warrant further clinical
ceivable that antiestrogens may help in restoring T levels in development [87]. Recently, results from another Phase II trial,
such a common condition. Clomiphene has also been shown this time placebo-controlled, were reported [88]. This study was
to revert HG in several other conditions, such as falciform conducted in obese men with sHG, but with a more severe
anaemia, uremia, alcohol and steroid abuse, and in the stimu- form than in the previous trials (total T < 8.67 nmol/l), and
lation of Gn secretion in patients with sulpiride-induced without having undergone T substitution. Two doses of enclo-
hyperprolactinemia and Gn suppression [69-74]. However, clomiphene were tested for 3 months (12.5 and 25 mg) and com-
miphene (25 -- 50 mg/day) is reported as ineffective in prepu- pared with T gel. Even in this placebo-controlled trial, both
bertal boys and, at high doses (500 mg/day), suppresses Gn doses of enclomiphene increase, to the same extent of T gel,
secretion even in normal adult males [75,76]. total T levels, however, with opposite effects on Gn, which
Two meta-analyses performed more than 10 years ago were reduced by transdermal T and stimulated by the antiestro-
failed to support a significant effect of different antiestrogens, gen. Sperm parameters, not always available, were maintained

Table 2. Characteristic and outcome summary of studies performed with mixed partial estrogen receptor agonists.
Author (year) Sample Population studied Age (yr) Drug Duration Serum TT Serum TT Serum LH Serum LH Serum FSH Serum Other
size of before ther- after ther- before ther- after ther- before ther- FSH after outcomes
treatment apy (nmol/l) apy (nmol/ apy (U/l) apy (U/l) apy (U/l) therapy
(days) l) (U/l)
Lim et al. 5 Chronic renal failure 48.6 CC 100 mg/d 150 -- 360 7.7 ± 5.7 30.5 ± 5.9 - - - - " serum FSH
(1976) [70] and LH
$ PRL
$ total
estrogen
$ sperm
concentration
Bjork et al. 1 Case report of 37 CC 50 -- 200 370 4.3 6.9 22.0 71.1 8.8 17.5 " estrogen
(1977) [72] Laennec’s cirrhosis mg/d " testis volume
" erectile
function
" ejaculation
Landefeld et al. 2 Case reports of 19 CC 50 -- 100 90 2.7 ± 1.2 9.1 ± 5.5 14.5 ± 6.4 82.8 4.3 ± 2.5 9.5 ± 2.1 " hematocrit
(1983) [71] sickle cell anaemia mg/d " Tanner stage
Ronnberg et al. 8 Healthy men 29 -- 49 CC 100 mg/d 7 - - 19.0 ± 1.4 16 ± 0.3 2.4 ± 0.6 2.3 ± 2.8 $ PRL
(1985) [74] 8 Healthy men with 29 -- 49 CC 100 mg/ 7 - - 19.0 ± 1.4 15 ± 0.3 2.4 ± 0.6 2.5 ± 0.6 # PRL
sulpiride-induced d + sulpiride # PRL induced
hyperprolactinemia 150 mg/d by TRH test
Guay et al. 17 Secondary HG men 60.5 CC 50 mg 3/wk 56 8.3 ± 1.3 18.3 ± 5.2 6.4 ± 1.5 10.2 ± 3.1 3.4 ± 1.4 5.6 ± 3.4 " measured free
(1995) [64] with ED T
$ sexual
function
$ nocturnal
tumescence
Tan et al. 1 Case report of 30 CC 100 mg/d 60 2.5 24.5 1.7 26.3 - - # HG related
(2003) [73] steroid abuse symptoms
Guay et al. 173 ED 54.3 CC 50 mg 3/wk 120 - - 3.9 7.9 - - " measured free
(2003) [65] T
" erectile
function
Shabsigh et al. 36 Infertile men 39.0 CC 25 mg/d 90 8.6 ± 1.4 21.2 ± 6.2 2.3 ± 2.3 - 7.5 ± 6.8 - " estradiol
(2005) [63]
Hussein et al. 42 Infertile men 29.6 CC 25 -- 75/d 155 - - - - 7.2 ± 7.9 7.9 ± 7.5 " sperm
(2005) [80] concentration
Whitten et al. 4 nIHH 30.5 CC 50 mg 3/wk NR 15.6 ± 23.8 21.4 ± 16.8 < 1.0 6.4 0.8 ± 0.01 3.5 ± 2.4 " sperm
(2006) [69] panhypopituitarism concentration
Age was reported as mean when available or range when mean value was not reported.
BMI: Body mass index; BMD: Bone mineral density; CC: Clomiphene citrate; d: Day; DA: Dopamine agonists; DHT: Dihydrotestosterone; ECC: Enclomiphene citrate; ED: Erectile dysfunction; FSH: Follicle-stimulating hormone; HDL: High-density
lipoprotein; HG: Hypogonadism; HOMA: Homeostatic model assessment; LDL: Low-density lipoprotein; LH: Luteinizing hormone; nIHH: Normo-osmic idiopathic hypogonadotropic hypogonadism; OGTT: Oral glucose tolerance test; PRL: Prolactin;
R: Raloxifene; SHBG: Sex hormone binding globulin; TC: Tamoxifene citrate; TRH: Thyrotropin-releasing hormone; To: Toremifene; TT: Total testosterone; yr: Years; wk: Week.
Table 2. Characteristic and outcome summary of studies performed with mixed partial estrogen receptor agonists (continued).
(days) l) (U/l)
Ribeiro and 14 Hyperprolactinemia 42.7 CC 50 mg/d 84 5.8 ± 3.1 11.4 ± 2.6 1.4 ± 1.5 4.1 ± 3.7 2.9 ± 3.4 5.6 ± 6.4 " estradiol
Abucham treated with DA " SHBG
(2009) [67] without correction of " calculated
T values free T
" erectile
function
" sperm motility
" BMD
$ fat mass
# triglycerides
" glycemia after
OGTT
Kadioglu 120 Infertile men 26.74 TC 20 mg/d 180 - - - - 5.7 ± 3.3 7.1 ± 5.2 " sperm
Tsourdi et al. 94 Infertile men - TC 20 mg/d 90 17.2 ± 6.1 26.5 ± 7.6 4.5 ± 1.8 7.8 ± 4.6 5.7 ± 2.7 8.4 ± 4.9 " sperm
99 Infertile men - To 60 mg/d 90 17.3 ± 5.4 25.8 ± 8.3 4.1 ± 1.9 6.5 ± 2.7 5.6 ± 3.4 9.5 ± 4.9 " sperm
concentration
91 Infertile men - R 60 mg/d 90 20.3 ± 5.6 20.9 ± 6.2 4.2 ± 1.7 4.8 ± 2.1 6.4 ± 3.4 6.9 ± 4.3 " sperm
concentration
Birzniece et al. 10 Healthy men 51 -- 77 R 60 mg/d 14 14.8 ± 3.2 18.6 ± 4.7 1.3 ± 0.3 1.6 ± 0.9 4.3 ± 2.2 5.7 ± 2.8 $ SHBG
(2010) [84] and 10 Healthy men 51 -- 77 R 120 mg/d 14 14.8 ± 3.2 18 ± 4.7 1.3 ± 0.3 1.6 ± 0.6 4.3 ± 2.2 5.3 ± 2.8 $ SHBG
(2012) [85] 10 Healthy men 51 -- 77 TC 10 mg/d 14 14.8 ± 3.2 18.6 ± 5.4 1.3 ± 0.3 1.7 ± 0.6 4.3 ± 2.2 5.5 ± 3.2 " SHBG
10 Healthy men 51 -- 77 TC 20 mg/d 14 14.8 ± 3.2 22.6 ± 6.3 1.3 ± 0.3 1.7 ± 0.6 4.3 ± 2.2 5.7 ± 2.8 " SHBG
Ribeiro and 9 Non-functioning 47.1 CC 50 mg/d 84 5.4 ± 2.8 2.9 ± 2.3 0.8 ± 0.6 1.1 ± 1.2 1.9 ± 3.0 2.8 ± 4.5 $ Estradiol
Abucham pituitary adenomas " BMI
(2011) [68] " fat mass
$ lean mass
$ glycemia
# HOMA
# total
cholesterol
Table 2. Characteristic and outcome summary of studies performed with mixed partial estrogen receptor agonists (continued).
(days) l) (U/l)
Katz et al. 86 Secondary HG men 29 CC 25 -- 50 mg/d 180 6.7 ± 3.0 16.8 ± 5.7 2.6 ± 2.2 6.8 ± 2.8 1.9 ± 1.7 7.6 ± 1.9 " measured free
(2012) [66] T
" estradiol
$ SHBG
# HG related
symptoms
Kaminetsky 8 Secondary HG men 46 ECC 25 mg/d 180 6.3 ± 0.3 17.7 ± 10.1 2.2 ± 1.0 6.0 ± 2.5 1.5 ± 0.4 5.2 ± 2.6 " estradiol
et al. (2013) [86] $ SHBG
" sperm
concentration
Wiehle et al. 12 Secondary HG men 53.3 ECC 6.25 mg/d 42 9.2 ± 3.2 13.6 ± 7.7 3.7 ± 1.8 6.0 ± 2.7 - - $ total
(2013) [87] cholesterol
$ HDL
cholesterol
$ LDL
cholesterol
$ triglycerides
7 Secondary HG men 53.3 ECC 12.5 mg/d 42 10.2 ± 2.8 14.8 ± 4.9 3.9 ± 1.2 6.9 ± 2.4 - - $ total
cholesterol
$ HDL
cholesterol
$ LDL
cholesterol
$ triglycerides
12 Secondary HG men 53.3 ECC 25 mg/d 42 8.8 ± 2.8 20.3 ± 5.0 4.5 ± 3.9 13.1 ± 7.0 - - $ total
cholesterol
$ HDL
cholesterol
$ LDL
cholesterol
$ triglycerides
Wiehle et al. 27 Secondary HG men 49.7 ECC 12.5 mg/d 90 7.5 ± 2.0 16.4 ± 6.4 4.4 ± 1.8 8.9 ± 4.4 6.4 ± 4.2 11.5 ± 8.7 " DHT
(2014) [88] " estradiol
$ SHBG
32 Secondary HG men 49.2 ECC 25 mg/d 90 7.3 ± 1.9 14.1 ± 5.7 5.3 ± 4.0 11.7 ± 8.1 9.4 ± 10.9 14.9 ± 10.4 " DHT
" estradiol
$ SHBG
Table 3. Mean difference in several clinical parameters after weight loss as derived from meta-analysis of the
available evidence.
Total testosterone CFT (pmol/l) SHBG (nmol/l) LH (U/l) FSH (U/l) E2 (pg/ml)
(nmol/l)
Low caloric diet 2.05 (0.95; 3.16)z

Bariatric surgery 10.15 (6.55;13.76)z
Overall 2.75 (1.69; 3.81)z 42.01 13.05 1.06 1.83 -- 6.95
(5.74; 78.28)z (5.24; 20.85)z (0.54; 1.57)z (1.13; 2.53)z (-- 12.2; -- 1.7)*
Data taken from [141].

*p < 0.01.
z
p < 0.0001.
CFT: Calculated free testosterone; E2: Estradiol; FSH: Follicular-stimulating hormone; LH: Luteinizing hormone; SHBG: Sex hormone binding globulin.
by enclomiphene and suppressed by T gel. However, a statisti- has been proven [94,95], no studies, so far, have evaluated their
cally significant improvement of sperm parameters was not effects on spermatogenesis. All these compounds stimulate
noticed after enclomiphene, most probably due to the short Leydig cells, and increase both intra-testicular and circulating
length of the trial. In this study, as well as in the previous T levels (see before). Considering that a high intra-testicular
ones, a significant rise of E2 levels was recorded, most probably T concentration is required for successful spermatogenesis,
due to the increased T substrate for aromatization and the some sHG patients can achieve or restore sperm production
obesity state. and fertility only using hCG alone, with a standard dosage
of 1000 -- 2000 IU intramuscular or subcutaneous injection
5.2.3 Aromatase inhibitors two to three times weekly [96]. However, when sperm concen-
Another possibility to increase T levels in subjects with tration in ejaculate is lower than 10 millions/ml, after 6 months
obesity-induced T deficiency is represented by the use of aro- of hCG alone, co-administration of FSH is required [96].
matase inhibitors. Loves et al. [89] investigated this possibility A recent meta-analysis [40] evaluating the available longitudinal
in an uncontrolled 6-month pilot study, performed in studies on achievement of spermatogenesis with Gn therapy in
12 severely obese men (BMI > 35 kg/m2). The treatment azoospermic sHG subjects showed an overall successful out-
with 2.5 mg letrozole once a week for 6 months reduced total come in 75% of patients, with a mean sperm concentration
E2 and increased serum LH and T levels. No information on achieved of almost 6 million/ml. Better results were obtained
sexual function was reported. More recently, the same group in patients with a postpubertal onset of sHG and in those
published the data of the first double-blind, placebo-con- with lower endogenous LH and FSH levels before starting
trolled, RCT in 42 obese men (BMI > 35 kg/m2) with a therapy [40].
serum total testosterone < 10 nmol/l [90]. All patients started Treatment with Gn, as an alternative to TRT, is also widely
on letrozole 2.5 mg/week, with subsequent dose escalation used for inducing androgenization of phenotype in subjects
every month until a serum total testosterone of 20 nmol/l with prepubertal onset of sHG [41]. Administration of hCG
was reached. Similarly to what has been previously reported, induces development of secondary sexual characteristics,
a decrease in E2 and an increase in T levels were observed. leads to testicular growth and, differently from TRT, it
However, no modifications of psychological symptoms as allows achievement of spermatogenesis [41]. hCG is usually
well as of metabolic parameters were detected [90]. Hence, injected (intramuscularly or subcutaneously) in a dosage
although aromatase inhibitors could theoretically represent of 1250-5000 IU weekly, alone or in combination with
an alternative option for the treatment of obesity-related 12.5 -- 150 IU of FSH weekly (Table 1) [41]. Despite the
male HG, the data published so far are too limited to suggest clinical advantages over TRT reported above, Gn therapy
their clinical use. In addition, the possible expected negative also presents disadvantages, such as modality of administra-
impact on bone density represents another major limitation tion, which is less convenient, and costs, as it is more expen-
for a long-term treatment [91]. sive than TRT. Hence, the use of Gn therapy in younger
subjects for a long time span is cumbersome.
5.3 Mimicking pituitary activity: Gn therapy Although the effectiveness of Gn has been extensively stud-
Gn therapy is the treatment of choice in men with sHG who ied in prepubertal onset sHG, its role in adulthood for the
require fertility (Tables 1 and 3). The most widely used com- treatment of LOH has been scarcely investigated. In a RCT
pound is hCG, purified from urine of pregnant women. involving 40 hypogonadal subjects, aged more than 60 years,
However, also recombinant hCG (rhCG [92]) and luteinizing Liu et al. [97-99] evaluated for the first time the effect of
hormone (rhLH [93]) are available. Although the efficacy of rhCG 5000 IU or placebo subcutaneously twice/week for
recombinant compounds in restoring T serum concentration 3 months. During the active treatment, the rhCG arm reached

G. Corona et al.
physiological total and calculated free T levels. As compared 5.4 Increasing Leydig cell steroid production,
with the placebo-treated arm, body weight and lean mass sig- independently from Gn stimulation
nificantly increased in the rhCG-treated patients, whereas fat 5.4.1 PDE5 inhibitors
mass decreased [97,98]. However, no difference in muscle Human testis expresses gene and protein for PDE5 [15,103],
strength was found between active-treated subjects and con- which, in the rat, has been immuno-localized in Leydig and
trols. Besides body composition, lipid profile also improved, peritubular myoid cells [104]. Although within the human testis
with a significant decrease in total and low-density lipopro- the gene expression of PDE5 is 10-fold lower than in penile
tein (LDL) cholesterol as well as triglycerides [98]. Conversely, corpora cavernosa [17], it still might have a physiological signif-
no difference was detected between rhCG-treated subjects icance. Accordingly, in the mouse, PDE5 inhibition, through
and controls in blood pressure, fasting glycemia and insuline- sildenafil dosing for 30 days, was able to increase androgen
mia as well as insulin sensitivity, as assessed by euglycemic levels [105,106]. In the rat, the effect of sildenafil on T secretion
hyperinsulinemic clamp [98]. No improvement of sexual was transient and apparent after 60 min, and mediated by a
function was observed [98]. Concerning bone metabolism, cGMP-dependent, PKG-induced phosphorylation of StAR
the short follow-up allowed only for the evaluation of bone [107]. However, in a rabbit model of MetS-induced HG we
biomarkers, and in rhCG-treated patients, in comparison were unable to demonstrate a significant increase in plasmatic
with controls, a higher level of neo-formation markers was T after short- [108] or long-term [109] exposure to tadalafil.
found, without differences in bone resorption markers [99]. In an open-label, retrospective study on 74 ED subjects it
Finally, no adverse event, including increased polysialic was found that 3-month treatment with either sildenafil or
acid, urinary symptoms or polyglobulia, was ascribable to tadalafil increased T levels by 2 -- 4 nmol/l [110]. In a recent
Gn treatment [96]. large RCT, it was found that a 4-week run-in of PDE5 inhib-
Similar results were reported later on by Tsujimura et al. itor (PDE5i), sildenafil, in hypogonadal men significantly
[100], who evaluated the effects of hCG in 77 sHG men aged
raised T levels by a mean of 4 nmol/l [111], supporting a pos-
50 -- 79 years complaining of consistent sexual, physical or sible role of PDE5i as the sole treatment in selected men pre-
psychological symptoms. They were treated for a mean time senting with ED and mildly reduced T levels. Although it is
of 8 months with intramuscular injections of hCG 3000 IU possible to hypothesize a direct action of PDE5 inhibition
every 2 weeks and a change in several symptoms and signs within the testis, these positive results could be explained
upon hCG treatment were considered. During follow-up, a also by the restored sexual activity, as demonstrated with other
significant improvement in sexual, physical and psychological treatments (see below). Accordingly, the short-term experi-
symptoms, as assessed by the Aging Males’ Symptoms (AMS) mental effects of sildenafil on Leydig cell T production [105-107]
scale, was observed [100]. However, no improvement of erectile could not be compared with the clinical findings reported in a
function was detected [100]. In addition, no difference in total study where subjects were taking on average two doses a
or high-density lipoprotein (HDL) cholesterol, as well as tri- week [111]. In addition, the possible role of TRT in improving
glycerides, was shown after hCG treatment [100]. The treat- PDE5i outcomes [112] confirms the limited power of these
ment was well tolerated and no significant side effects were classes of drugs in improving T levels.
reported [100]. It must be noted that the dosage used in this
study was significantly lower than that commonly used in
replacement of sHG. Accordingly, total and calculated free 5.4.2 PBR/TSPO agonist
T levels, measured after therapy, although significantly higher PBR/TSPO agonist ligands, including BDZ with TSPO
than baseline levels, were barely above the lower limit of the binding activity [113], stimulate steroidogenesis by facilitating
normal range [100]. cholesterol delivery to the cytochrome P450 side-chain cleav-
Hence, data on hCG treatment of LOH are still scanty and age enzyme in the inner mitochondrial membrane [114]. It has
studies comparing TRT and Gn are not available. However, been demonstrated that the PBR/TSPO agonist PK11195
Gn seems to be a reasonable alternative also for treatment of stimulates steroidogenesis in the Y1 mouse adrenal tumor
postpubertal forms of sHG when fertility is required. They cell line and that the targeted disruption of PBR/TSPO in
stimulate steroidogenesis overall with possible effects due to the R2C rat Leydig tumor cell line inhibits steroidogenesis
steroids other than T, such as E2 and DHT [101]. In addition, (see for review [114]). However, Leydig cell-specific TSPO
it is unlikely to reach excessively high T levels, since Gn’s conditional knockout mice suggested that TSPO was not
effect is limited by Leydig cell capacity [102]. Finally, Gn is required for T production in vivo [115,116]. In order to clarify
well tolerated and adverse events are infrequent and include the definitive role of TSPO in steroidogenesis and embryo
an increased incidence of gynecomastia, development of anti- development, global TSPO null (TSPO-/-) mice were gener-
bodies limiting pharmacological action and hypersensitivity ated. TSPO-/- mice survived with no apparent phenotypic
reactions [41]. However, the required high frequency of injec- abnormalities and were fertile [110]. Although BDZ have
tions and the lack of sufficient information in improving been on the market for several decades, and most of them
LOH-related symptoms represent the major limitations for bind to PBR/TSPO, no stimulating effects on T synthesis of
long-term use. this class of drugs have been reported in humans. Hence,

the role of PBR/TSPO agonist in the treatment of HG is weight reduction after bariatric surgery. However, the number
more than hypothetical. of patients evaluated and their follow-up are too limited to
draw any conclusions. Interestingly, we recently meta-analyzed
5.5 Non-pharmacological options to increase T levels available evidence on the effect of weight loss on sex steroid
5.5.1 Restoring sexual activity hormone levels and obesity-associated sHG [141]. Both low
The fact that sexual activity per se can affect T levels has been caloric diet and bariatric surgery were associated with a signif-
hypothesized since the 1970s [117]. During the following years, icant increase in circulating SHBG and total T levels, with bar-
only scanty reports substantiated this anecdotical report, dem- iatric surgery more effective than diet [141]. Similarly, weight
onstrating, during sexual intercourse [118,119] or exposure to loss was associated with an increase of both LH and FSH levels
erotic movies [120], a timely related rise in T level. However, as well as with a reduction of E2 circulating levels (Table 3) [141].
other studies addressing the question of a sexual activity- Multiple regression analysis shows that the degree of body
induced rise in T plasma levels were negative [121-125]. Jannini weight lost was the best determinant of total T rise
et al. showed that restoring erection by non-hormonal inter- (B = 2.50 ± 0.98; p = 0.029), whereas quite unexpectedly, no
vention (behavioural therapy, intracavernous injections) res- effect of E2 decrease after weight loss on total T was observed.
cued an otherwise borderline low T level by 30 -- 40% of In line with the latter observation, when a cohort of 55 mor-
baseline values [126]. The T rise they found was independent bidly obese men observed at 6 and 9 months after different
from the kind of therapies used, but strictly related to the suc- types of bariatric surgery was stratified according to the pres-
cessful outcome of therapeutic intervention. Hence, they ence of overt HG (total T < 8.0 nmol/l), the increase in andro-
speculated that sexual inactivity resets reproductive axis to a gen levels (total and free T) was significant only in HG
lower activity, somehow inducing a sHG, characterized by a subjects [142]. Moreover, a decrease in E2 levels was observed
reduced LH bioactivity [126,127]. In agreement with this only in eugonadal subjects, having higher E2 levels at baseline.
hypothesis, we observed that sexual inactivity -- induced by Hence, the role of E2 in the determination of obesity-related
bilateral cavernous neurotomy -- was associated with an overt HG is smaller than what has been previously hypothesized [3].
condition of HG, characterized by reduced T plasma level, In fact, in eugonadal subjects, the reduction in E2 determined
reduced ventral prostate weight, reduced testis function by surgery does not produce an increase in T, whereas recovery
(including testis weight and number of Leydig cells), with of HG occurs without any significant increase in E2 levels.
an inadequate compensatory increase of LH [128]. In addition, Hence, other fat-associated factors, besides estrogens, can be
in a consecutive series of 2302 male patients with ED, sexual speculated to mediate the weight reduction-induced improve-
inactivity was associated with overt HG [129]. Hence, it is ment in T levels. However, it should be recognized that in all
plausible that increasing sexual activity might ameliorate the previous studies serum E2 was evaluated using direct
HG, at least in the milder forms. immunoassays which are not considered the gold standard in
men [143]. Hence, E2 data would have overlooked the inaccu-
5.5.2 Lifestyle modifications racy and method-specific bias.
The association between LOH and adverse metabolic condi-
tions, such as obesity, MetS and T2DM, is well known [130,131], 6. Conclusion
with a rather complex, and often multidirectional, pathoge-
netic background. Several studies have demonstrated that, in Adulthood HG is the most common form of male HG and
individuals at risk, intensive lifestyle intervention, along with includes both central and peripheral derangements. TRT is
nutritional counseling and physical activity is able to reduce the most commonly used and most simple way to treat male
weight loss and insulin resistance, preventing the progression HG. In addition, it represents the advisable therapy for pri-
to overt diabetes [132-137]. Similarly, weight loss per se [138], mary HG. However, for the secondary or mixed forms several
along with lifestyle modifications, is able to improve sexual alternative possibilities can be offered, according to patient-
function, although only limited data have been published so related outcome, including the fertility status. These possibili-
far [138,139]. Unfortunately, diet and behavioural therapies often ties range from removing the HG-associated morbidities
ultimately fail [140]. Bariatric surgery is another option pro- (MetS, T2DM), encouraging lifestyle modifications (increas-
posed to rapidly lose weight in the presence of morbidly obesity ing sexual activity, weight loss) or medical therapy. The latter
and important associated morbidities [140]. In line with the includes medications that decrease the estrogen-negative feed-
aforementioned evidence, according to the Standard Operating back (antiestrogens) or that activate the hypothalamus--
Procedures of the International Society for Sexual Medicine, pituitary--testis axis (GnRH agonists and Gn). Antiestrogens
lifestyle modifications should be strongly encouraged in all are not approved for the treatment of male HG, although for
hypogonadal subjects with obesity, T2DM and MetS [3]. How- one molecule, enclomiphene, the FDA review is pending. In
ever, only few randomized clinical studies have specifically eval- addition, an intact hypothalamus--pituitary axis is required
uated the impact of diet and physical activity on T levels in for the successful outcome of antiestrogens. Conversely, the
men [141]. Conversely, data that are more robust suggest an possibility of increasing Leydig cell steroid production,
increase of T level, strictly dependent on baseline BMI and independently from Gn stimulation such as in the case of

G. Corona et al.
PDE5is or PBR/TSPO agonist ligands, seems unreliable at the recent meta-analysis indicates that this class of compounds is
moment. able to increase sperm production and pregnancy rate [80], how-
ever, their effect are less dramatic than with Gn. Among anties-
7. Expert opinion trogens, enclomiphene is the most interesting molecule, as it is
specifically designed and tested for the treatment of sHG.
A thorough understanding of the nature of male HG is manda- Enclomiphene was shown to improve hormonal levels, sexual
tory before choosing treatment options (Box 1). Considering activity and sperm production; however, the number of dedi-
that sHG is dramatically more prevalent than the primary cated studies is still limited. For primary HG no alternative
form and that the former often arises from the presence of obe- strategy to T is available, but it is important to say that, in
sity or other chronic disturbances, careful screening of such this condition, preserving fertility is not a problem, because it
conditions is important not only to improve the HG status, is compromised by definition.
but also for general health. For example, a complete recovery This box summarizes key points contained in the article.
of severe HG (T < 8 nmol/l) was observed in 93% of morbid
obese subjects undergoing bariatric surgery [142]. However, Declaration of interest

when fertility is urgently required by a HG subject, lifestyle
modification does not offer satisfactory results. Håkonsen G Corona has received consultancies from Bayer, Besins,
et al. [144]. did not observe any modification in sperm concen- Otsuka, Eli-Lilly and Menarini. M Maggi has received con-
tration in obese subjects after 14 weeks of a weight loss pro- sultancies from Bayer, Prostrakan, GSK, Eli-Lilly and Menar-
gram, even if a T and Gn rise was observed. Hence, in this ini. The authors have no other relevant affiliations or financial
framework, Gn or GnRH therapy is the correct choice. involvement with any organization or entity with a financial
A recent meta-analysis indicates that three out of four azoosper- interest in or financial conflict with the subject matter or
mic subjects with sHG obtain sperm after Gn or GnRH sup- materials discussed in the manuscript apart from those
plementation. An alternative option is antiestrogens. Another disclosed.
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141. Corona G, Rastrelli G, Monami M, E-mail: m.maggi@dfc.unifi.it
et al. Body weight loss reverts obesity- 144. Håkonsen LB, Thulstrup AM,
associated hypogonadotropic Aggerholm AS, et al. Does weight loss
hypogonadism: a systematic review and improve semen quality and reproductive

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Review

The pharmacotherapy of male

Keywords: antiestrogens, gonadotropin, male hypogonadism, testosterone

Expert Opin. Pharmacother. (2015) 16(3):369-387

(sHG) in adults [6]. Neurokinin-B is co-expressed with

phosphodiesterase type 5 inhibitors. 2. Testicular testosterone formation

The binding of LH, or of its structurally related molecule,

370 Expert Opin. Pharmacother. (2015) 16(3)

Andrologic and estrogenic effect

External and internal

Expert Opin. Pharmacother. (2015) 16(3) 371

372 Expert Opin. Pharmacother. (2015) 16(3)

Table 1. Available preparations to treat male hypogonadism.

Compound Trade name Standard dosage Advantage Disadvantages

Recombinant No data on infertile men

Expert Opin. Pharmacother. (2015) 16(3) 373

374 Expert Opin. Pharmacother. (2015) 16(3)

Expert Opin. Pharmacother. (2015) 16(3) 375

Low caloric diet 2.05 (0.95; 3.16)z

Data taken from [141].

Expert Opin. Pharmacother. (2015) 16(3) 379

380 Expert Opin. Pharmacother. (2015) 16(3)

Expert Opin. Pharmacother. (2015) 16(3) 381

obese subjects undergoing bariatric surgery [142]. However, Declaration of interest

382 Expert Opin. Pharmacother. (2015) 16(3)

1978;9:194-200 guideline. J Clin Endocrinol Metab nonapeptide KISS1R agonists with

Expert Opin. Pharmacother. (2015) 16(3) 383

hypogonadotropic hypogonadism. J Clin oligozoospermia. Fertil Steril Hypogonadism. J Sex Med

58. Filippi S, Luconi M, Granchi S, et al. fails to revert hypogonadism in most

384 Expert Opin. Pharmacother. (2015) 16(3)

2013;1:749-57 hypogonadism. Eur J Endocrinol et al. Do reproductive hormones modify

Expert Opin. Pharmacother. (2015) 16(3) 385

1978;40:166-72 Fowler SE, et al. Reduction in the

386 Expert Opin. Pharmacother. (2015) 16(3)

on clinical association studies in men. Italy;

Expert Opin. Pharmacother. (2015) 16(3) 387

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