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"Cherchez La Femme": Modulation of Estrogen Receptor Function With Selective Modulators: Clinical Implications in the Field of Urology

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Introduction: Selective estrogen receptor modulators (SERMs) have been used off-label in men for more than 50 years. SERMs exert their action on the estrogen receptor agonistically or antagonistically. A fundamental knowledge of the complex molecular action and physiology of SERMs is important in understanding their use and future directions of study in men. Aim: To review the basic science and mechanism of the action of estrogens, the estrogen receptor, and SERMs, and the existing clinical publications on the use of SERMs in men for infertility and hypogonadism with their strengths and weaknesses and to identify the need for future studies. Methods: After a review of publications on the basic science of estrogen receptors, a chronologic review of published evidence-based studies on the use of SERMs in men for infertility and hypogonadism was undertaken. Main outcome measures: Clinical publications were assessed for type of study, inclusion criteria, outcome measurements, and results. Strengths and weaknesses of the publications were assessed and discussed. Results: Few prospective rigorously controlled trials have been undertaken on the use of SERMs in men. Most existing trials are largely retrospective anecdotal studies with inconsistent inclusion and end-point measurements. The SERMs are complex and at times can produce paradoxical results. Their action likely depends on the genetics of the individual, his tissue-specific composition of estrogen receptors, the molecular structure and pharmacodynamics of the SERMs, and their metabolism. Conclusion: Rigorously controlled trials of the use of SERMs in men are needed to better identify their clinical benefit and long-term safety in infertile and hypogonadal men. Recent placebo-controlled pharmaceutical industry SERM trials have demonstrated short-term safety and efficacy in men with secondary hypogonadism and eventually might provide an alternative to exogenous testosterone replacement therapy in men with secondary hypogonadism. Helo S, Wynia B, McCullough A. "Cherchez La Femme": Modulation of Estrogen Receptor Function With Selective Modulators: Clinical Implications in the Field of Urology. Sex Med Rev 2017;X:XXX-XXX.
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Cherchez La Femme: Modulation of Estrogen Receptor Function With
Selective Modulators: Clinical Implications in the Field of Urology
Sevann Helo, MD,
1
Blake Wynia, MD,
1
and Andrew McCullough, MD
2
ABSTRACT
Introduction: Selective estrogen receptor modulators (SERMs) have been used off-label in men for more than 50
years. SERMs exert their action on the estrogen receptor agonistically or antagonistically. A fundamental
knowledge of the complex molecular action and physiology of SERMs is important in understanding their use
and future directions of study in men.
Aim: To review the basic science and mechanism of the action of estrogens, the estrogen receptor, and SERMs,
and the existing clinical publications on the use of SERMs in men for infertility and hypogonadism with their
strengths and weaknesses and to identify the need for future studies.
Methods: After a review of publications on the basic science of estrogen receptors, a chronologic review of
published evidence-based studies on the use of SERMs in men for infertility and hypogonadism was undertaken.
Main Outcome Measures: Clinical publications were assessed for type of study, inclusion criteria, outcome
measurements, and results. Strengths and weaknesses of the publications were assessed and discussed.
Results: Few prospective rigorously controlled trials have been undertaken on the use of SERMs in men. Most
existing trials are largely retrospective anecdotal studies with inconsistent inclusion and end-point measurements.
The SERMs are complex and at times can produce paradoxical results. Their action likely depends on the
genetics of the individual, his tissue-specic composition of estrogen receptors, the molecular structure and
pharmacodynamics of the SERMs, and their metabolism.
Conclusion: Rigorously controlled trials of the use of SERMs in men are needed to better identify their clinical
benet and long-term safety in infertile and hypogonadal men. Recent placebo-controlled pharmaceutical
industry SERM trials have demonstrated short-term safety and efcacy in men with secondary hypogonadism
and eventually might provide an alternative to exogenous testosterone replacement therapy in men with
secondary hypogonadism. Helo S, Wynia B, McCullough A. Cherchez La Femme: Modulation of
Estrogen Receptor Function With Selective Modulators: Clinical Implications in the Field of Urology. Sex
Med Rev 2017;X:XXXeXXX.
Copyright 2017, The Authors. Published by Elsevier Inc. on behalf of the International Society for Sexual Medicine.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Key Words: Estrogen Receptor; Selective Estrogen Modulator; Male Infertility; Secondary Hypogonadism
INTRODUCTION
The biologic effects of estrogen in the male physiology are
extensive (bone health, sexual behavior, fertility, gonadotropin
[GTP] feedback, lipid regulation, endothelial health, and
regulation of fat stores).
1
A great deal has been learned about the
importance of estrogen in men with aromatase deciency and
estrogen resistance syndromes. The treatment of infertility and
hypogonadism (HG) through the modulation of estrogen levels
through the use of aromatase inhibitors
2
or selective estrogen
receptor modulators (SERMs) has been used off-label in men for
decades.
3
This review focuses on the use of SERMs. The purpose
of this review is to provide the reader with a basic science
background of the mechanism of action of estrogen as a ligand
and the estrogen receptor (ER), a review of congenital estrogen
resistance syndrome and ER polymorphism, and a comprehen-
sive review of the use of SERMs in the treatment of male
infertility and HG. For a general review of the preclinical role of
estrogens in men, the reader is directed to two excellent reviews
by Rochira et al
4
and Luconi et al.
1
Received December 7, 2016. Accepted March 4, 2017.
1
Albany Medical College, Albany, NY, USA;
2
Lahey Health Center, Burlington, MA, USA
Copyright ª2017, The Authors. Published by Elsevier Inc. on behalf of
the International Society for Sexual Medicine. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).
http://dx.doi.org/10.1016/j.sxmr.2017.03.003
Sex Med Rev 2017;-:1e22 1
AN EVOLUTIONARY PERSPECTIVE OF
ESTROGENS AND THEIR RECEPTORS
If you want to understand today, you have to search
yesterday.
Pearl Buck (1892e1973)
Through advanced genomics, proteomics, and DNA
sequencing, much has been learned about the evolution of the
nuclear ER and its estrogen ligand. The evolution of the ER and
the cytochrome (CYP) P450 enzyme aromatase, which is
responsible for the production of estrogen, is linked to the
emergence of chordates (animals with a backbone). It is highly
probable that the two evolved independently of each other and
through the trial-and-error process of evolution became highly
interdependent and complex. The machinery for the production
of estrogen starts with the CYP450 superfamily. The CYP450
enzyme class is one of the oldest evolutionarily, having been
present in unicellular organisms more than 3.5 billion years ago.
5
CYP450s support the oxidative, peroxidative, and reductive
metabolism of endogenous substrates, environmental pollutants,
and steroids. It presumably served a protective detoxifying
purpose to the unicellular organisms. Gene bank research has
not detected the enzymes responsible for the cholesterol
side-chain cleavage to pregnenolone (CYP11A) or aromatase
(CYP19) before the pre-chordate amphioxus sh (450 million
years ago) and vertebrates.
6
Nonetheless, 17b-hydroxysteroid
dehydrogenaseerelated genes (ie, homologues) without clear
substrates have been found in invertebrates, suggesting inde-
pendent evolutionary pathways in vertebrates and non-
vertebrates. Despite many searches for human-type steroids in
non-vertebrates and the occasional report of the existence of
estrogen in insects,
7
the enzymes involved in their biosynthesis
have not been characterized.
8
Considering the importance of
estrogens in bone metabolism, it is not surprising that aromatase
might have played a role in the evolution of vertebrates.
At the same time that pre-vertebrates were developing the
cellular machinery to make the estrogen ligand, the ER, its target,
was evolving. The ER has been found to have genomic and non-
genomic functions. The phylogeny of the non-genomic function
of the ER and its ligand are less well studied. The ER belongs to a
family of nuclear receptors, referred to as the steroid/thyroid
nuclear receptor superfamily,originating from an ancient
nuclear receptor 400 million years ago. Nuclear receptors share
several structural domains; these include the hypervariable region
(Figure 1A, B), the DNA-binding domain (DBD; Figure 1C),
the hinge region (Figure 1D), and the ligand-binding domain
(LBD; Figure 1E, F). In the nuclear receptor superfamily, the
DBD is highly conserved, whereas the LBD is moderately
conserved. It is highly probable that the ligand-specic nuclear
receptors arose from ancestral orphan nuclear receptors,
nuclear receptors that do not bind a ligand or the ligand has yet
to be identied. Through gene mutations and duplications, the
nuclear receptors developed the ability to interact and bind
ligands with stereospecicity.
9
The ER is believed to be the
ancestral steroid receptor from which the androgen, mineralo-
corticoid, glucocorticoid, and progesterone receptors evolved
through gene duplications. The early evolutionary presence of
the gene and protein does not imply that the function of the ER
functioned in its current way in relation to sexual dimorphism.
The estrogen and its receptor might have contributed to the
development of a more complex brain and the development of
the bony skeleton.
10
The ER found in the pre-vertebrate lancelet
does not bind the estrogen molecule and the ligand domain
shares 61 of 66 amino acid residues with the human ERa.
11
In the lamprey, estrogen is the only functional sex steroid
because the lamprey testis does not even bind testosterone (T).
The androgen receptor likely arose by gene duplication after the
lamprey lineage diverged from other vertebrates and the hor-
monal control over sexual dimorphism is a relatively recent
evolutionary event.
6
Over time, the ER evolved into a highly complex molecular
structure. It resides in the cell nucleus as a monomer ERaor
ERb. Interaction with the ligand (estrogen, antiestrogen, or
SERMs) results in physicochemical changes in the receptor
leading to conformational changes with concomitant dissociation
of the heat shock proteins and subsequent dimerization and
interaction with specic DNA sequences (estrogen response
elements [EREs]) on target genes. The DNA receptor complexes
interact with the transcriptional complex and with corepressor or
coactivator proteins depending on the cellular context. This
interaction results in a DNA complex that signals as a turn off
or a turn onof transcription (Figure 2). The end functional
result is dependent on the tissue-specic molecular composition
Figure 1. Estrogen receptor domains. Panels A and B show the N-terminal A/B domain containing the ligand-independent transcriptional-
activation function. Panel C shows the DNA-binding domain. Panel D shows the hinge region domain. Panel E shows the hormone-binding
domain and the ligand-dependent transcriptional-activation function. Panel F shows the C-terminal. The percentages of homology between
the corresponding domains of the two different estrogen receptors are indicated.
Sex Med Rev 2017;-:1e22
2Helo et al
as a homodimer (ERa-ERa,Erb-Erb) or as a heterodimer
(ERa-Erb), its afnity for the steroid ligand, and interaction with
specic EREs and coactivators that can suppress or enhance gene
transcription. Although ERaalmost always results in gene acti-
vation, ERbacts by inhibiting transcription. Tissue-specic
concentrations of the two ER species and individual genetic
polymorphisms will result in tissue-selective mixed agonistic and
antagonistic and differential effects of the SERMs in different
tissues and individuals.
12
IMPLICATIONS OF ER ABSENCE IN MALE HUMAN:
CONGENITAL ESTROGEN RESISTANCE
To more fully understand the role of estrogen and its effect of
binding of the ER in the male animal, it is helpful to examine the
consequences of mutations in estrogen resulting in estrogen
resistance. There have been two instances of a genetic mutations
leading to estrogen resistance that have been reported in
men.
13,14
The rst patient was a 28-year-old man who initially
presented for evaluation of genu valgum and tall stature (80.3
inches).
1
He had normal pubertal development and growth but
then continued to grow in stature after the conclusion of
puberty. Physical examination showed no abnormal ndings
other than tall stature and increased pigmentation of the skin of
each axilla, with bilaterally descended testes of normal size
(20e25 mL each) and a normal-size prostate. Plain lms showed
a bone age of only 15 years, and he had minimal evidence of
epiphyseal maturation. The patient had signicantly decreased
bone mineral density, with a dual-energy x-ray absorptiometric
scan showing a density of 3.1 SDs below the mean for age-
matched normal women. Although he had a normal karyotype
(46,XY), he had increased levels of 17b-estradiol (E2; 119 pg/mL),
follicle-stimulating hormone (FSH; 33 mIU/mL), and luteinizing
hormone (LH; 37 mIU/mL). Despite the increased E2, serum T
level was normal (445 ng/dL), and semen analysis showed a sperm
count (SC) of 25 million/cm
3
.
The investigators hypothesized that the patients increased
serum estrogen and GTP concentrations might be explained by
primary estrogen resistance; as such, he was placed on a regimen
of transdermal E2. Although the patients serum E2 did increase,
Figure 2. Estrogen receptor action. Each class of SERMs (orange symbols) has a slightly different shape, although all will bind to the
estrogen receptor. When it binds to an estrogen, antiestrogen, or SERM, the estrogen receptor undergoes a conformational change that
permits its spontaneous dimerization and facilitates the subsequent interaction of the dimer with EREs located within target genes. The
estrogen receptor-ligand complex also leads to binding of various coregulator proteins that vary with its conformational structure. Some
estrogen receptor-SERM complexes favor corepressor recruitment (red) that, in a given target cell, increases its antagonist activity, and
others favor coactivator recruitment (blue) that increases its agonist activity. Some SERMs also can facilitate the interaction of the
estrogen receptor with yet-to-be-identied coactivators (green) with which estrogens or antiestrogens would not normally couple. It has
been determined that estrogen facilitates the interaction of the estrogen receptor with coactivators. The antagonist-activated estrogen
receptor interacts preferentially with corepressors. The binding of different SERMs to the receptor permits the receptor to adopt
conformational states that are different from each other and distinct from that induced by classic estrogen agonists or antagonists. The
implication of this model is that SERM activity will be inuenced by the relative levels of expression of the coregulator proteins
(corepressors and coactivators) that are expressed in different target cells. From Riggs and Hartmann.
12
EREs ¼estrogen response
elements; SERMs ¼selective estrogen receptor modulators.
Sex Med Rev 2017;-:1e22
Cherchez La Femme3
his GTPs were unchanged, suggesting pituitary or hypothalamic
insensitivity and no signicant increase in the serum concen-
tration of any of the estrogen-dependent proteins (sex hormone,
thyroxin, cortisol-binding globulins, and prolactin). In addition,
there were no changes in bone turnover markers of demineral-
ization, bone mineral density, or evidence of epiphyseal matu-
ration. At DNA sequencing, he was found to have a variant
banding pattern in exon 2 of the ER gene Esr1 with the
substitution of cytosine for thymine at codon 157 of the two
alleles coding for the ER resulting in a premature stop codon.
The translated protein would be lacking the DBD and LBD
(E2). Further analysis of the patients family showed that his
parents were heterozygous carriers for this mutation, leading to
the conclusion that the mutation was inherited in an autosomal
recessive fashion. Despite being a non-smoker, having normal
blood pressure, and demonstrating normal cholesterol concen-
trations, he was found to have impaired ow-mediated endo-
thelium-dependent vasodilatation in his peripheral vasculature
and early atherosclerotic coronary artery disease.
15,16
The nd-
ings highlight the importance of estrogen for bone maturation
and mineralization, in addition to cardiovascular risk, in men.
The patient was treated with bisphosphonates for his osteopenia;
his open epiphysis and genu valgum were corrected with a wedge
resection of the distal femur but he was lost to follow up. No
information is known about his fertility.
17
A second case of an ER mutation leading to estrogen resistance
in an 18-year-old man was recently been reported with a very
different phenotypic presentation.
14
The patient presented with
his two older sisters for lack of pubertal development. He was
found to have Tanner stage 1 gonadal development with a
cryptorchid right testis and a severely hypoplastic left testis
(<1 mL). He was 64 inches tall with the bone age of an 11-year-
old boy. He had increased E2 (59 pg/mL), LH (13 IU/L), and
FSH (56 IU/L) levels and low total T (86 ng/dL) and inhibin
B (5 pg/mL) levels. At genetic analysis, all three siblings were
found to have a homozygous missense mutation in the fth
coding exon of Esr1. The result was a pivotal amino acid sub-
stitution in a highly interspecies conserved region of the LBD of
ERa(histidine for arginine) and a 65-fold decreased binding of
E2 to the receptor. None of the ERaligands (ethinyl-E-2,
diethylstilbestrol, raloxifene [RAL], clomiphene, and tamoxifen
[TF]) were able to restore estrogen responsiveness.
14
The differences in phenotypic presentation with poly-
morphism of the ER and Esr mutations and the differential tissue
expression of the ER underscore the complexity of the ER and
the potential of a spectrum of different results of any therapeutic
modality acting as an ER agonist or antagonist.
ER POLYMORPHISMS IN MALE FERTILITY AND
IMPLICATIONS
Several studies during the past 15 years have examined the
relation between ER polymorphisms and semen quality.
18e21
In a 2002 study, Kukuvitis et al
20
genotyped 173 Greek men
(109 men with oligospermia or azoospermia and 64 controls) for
two polymorphisms of ERa. Those with azoospermia or idio-
pathic severe oligospermia were found to have signicantly larger
numbers of the Xba1 polymorphism of ESR1 (the ERagene)
than controls. Although limited by a small sample and by the
restricted ethnic composition of the population, this study rst
raised the possibility of genetic polymorphisms of the ER
affecting male fertility. One can only assume that this type of
polymorphism might be responsible for the potential differing
effect in men taking SERMs.
Since that study, several other studies have examined the
relation between ER mutations and male fertility. In a 2006
study, Guarducci et al
19
found that in men with the (TA)
n
repeat
polymorphism in the promoter region of ESR1, the mean TA
repeat number was inversely correlated with sperm concentra-
tion. In a subsequent analysis of 303 Taiwanese men, Su et al
21
found a lower sperm concentration in those with the rs180113
ESR1 polymorphism and the rs1256049 ESR2 polymorphism.
A recent well-designed meta-analysis of the strength of the
relation between the four most commonly researched single-
nucleotide ER polymorphisms (ESR1: PvuII, XbaI; ESR2: RsaI,
and AluI) and male infertility was conducted by Ge et al.
18
The
ndings showed a strong ethnic inuence on the effect of the
single-nucleotide ER polymorphisms on spermatogenic failure.
ESR1 PvuII and XbaI and ESR2 RsaI polymorphisms demon-
strated a decreased risk of spermatogenic failure in the Asian
cohort vs an increased risk in the Caucasian cohort. No signi-
cant association was detected in the overall analysis or subgroup
analyses by ethnicities and genotyping methods for the ESR2
AluI polymorphism. Although the strength of conclusions of this
meta-analysis is limited by small samples, limited ethnic diversity
within studies, and signicant between-study heterogeneity, the
study provides further evidence that advances in genetic testing
might help identify those most likely to be helped by SERMs or
explain differing or paradoxical results or side effects.
THE LIGAND
ER Ligands and Afnity
Knowledge of individual ER ligands and their afnity for the
receptor are crucial when understanding the effects of endoge-
nous estrogen and synthetic compounds on specic organ
systems. Endogenous estrogens in humans are found in three
forms: estrone (E1), E2, and estriol (E3). E1 and E3 are 1/12th
and 1/80th the potency of E2, respectively
22
(Figure 3A). The
hydroxyl groups at either end of the estrogenic steroidal back-
bone are crucial in binding to charged amino acids within the
hydrophobic core of the ligand-binding pocket. Among these, E2
has by far the greatest afnity for the ERs, with dissociation
equilibrium constants (ie, K) of 0.04 nmol/L for ERaand
0.11 nmol/L for ERb. E2 is 80 and 12 times more potent than
E3 and E1, respectively.
23
Approximately 35 to 45 mg
(0.130e0.165 mmol) is produced daily by the male human.
24,25
Sex Med Rev 2017;-:1e22
4Helo et al
Although 20% of the estrogen is produced by the testis, 60% of
the circulating E2 is derived from testicular secretion or
conversion of testicular androgens, and the balance (40%) is
from conversion of adrenal androgens.
26
E2 is bound to SHBG,
but the binding afnity for T to SHBG is almost twice that of
estrogen (K
m
¼1.68 vs 68). As T increases with SERM treat-
ment, free E2 is released from SHBG.
27
Synthetic estrogens such as diethylstilbestrol (Figure 3B) have
been produced that have a similar afnity for the two ER sub-
types as E2 (K
m
¼0.04 for ERaand 0.05 for ERb) yet can
demonstrate a fourfold relative binding afnity for the ER vs
E2.
28,29
The role of ERs in breast and uterine cancers, osteo-
porosis, and cardiovascular disease led to the development of
synthetic molecules to modulate the estrogen signaling mecha-
nism (antiestrogen).
30
There are two types of antiestrogens,
SERMs and selective estrogen receptor down-regulators
(SERDs). The SERMs are so named because of their tissue-
specic agonistic or antagonistic activity and include TF and
its analogues (Figure 3C). The SERDs induce accelerated
proteosomal degradation of ERaand act as pure antiestrogens
devoid of partial agonistic activity. That being said, some SERMs
have some SERD activity (RAL, bazedoxifene). Alterations in the
shorter side chains of SERMs (Figure 3B) result in more SERD
activity interference with conformational changes in the ER
required for ER agonistic properties.
30
The development of new
SERMs with SERD activity is an active area of research for the
treatment of breast cancer. This review focuses on the SERMs
that have been used in men.
30
Stereoisomers (cis vs trans) within
the manufactured SERMs likewise can affect ER agonistic vs
antagonistic properties (enclomiphene [EC] vs zuclomiphene
[ZU]; Figure 3D).
31
The afnity of SERMs currently used for the treatment of male
infertility and HG has not been studied with respect to afnities
for the individual ER subtypes (aand b) in the human. However,
afnity of TF citrate, toremifene (TOR), and clomiphene citrate
(CC) for the entire ER subfamily has been studied in a rat model,
with these compounds displaying relative binding afnities for the
ER of 1.6%, 1.38%, and 0.72%, respectively, in relation to E2.
29
Nonetheless, the peak serum concentration of TF at 20 mg/d is
120 ng/mL (122,000 pg/mL) vs E2 24 pg/mL in the average man
(almost a threefold order of magnitude molar difference),
32
thus
possibly overwhelming the receptors stoichiometrically.
The ER and Its Mechanism of Action
ERaand ERbare encoded by separate genes (ESR1 and ESR2,
respectively) on chromosomes 6 and 14, respectively.
33
Each is
composed of six domains (Figure 1AeF) with specic functions.
These regions are the N-terminal A/B transactivation domain
Figure 3. Comparative structures of natural and synthetic estrogen and selective estrogen receptor modulators. Panel A shows naturally
occurring estrogens. Panel B shows the synthetic estrogen diethylstilbestrol. Panel C shows selective estrogen receptor modulators.
Panel D shows cis- and trans-stereoisomers of clomiphene citrate (enclomiphene and zuclomiphene).
Sex Med Rev 2017;-:1e22
Cherchez La Femme5
(Figure 1A, B), the DBD (Figure 1C), the hinge region
(Figure 1D), and the LBD (Figure 1E, F).
34
ERais a protein of
595 amino acids with a molecular weight of 66 kDa, whereas ERb
is smaller with a molecular weight of 54 kDa. There are two splice
variants of ERb,ERb1andERb2, each with different patterns of
expression in various tissues and differing afnities for E2.
1
The N-terminal A/B domain is involved in the non-ligand
transcriptional activation of target-gene expression and the
interaction with coregulator proteins.
35
The A/B region also
contains the activation function-1 (AF-1) domain and several
amino acids that are targets for post-translational modications
and is the least conserved between receptors (17%).
1
Post-
translational functions include phosphorylation, acetylation, and
methylation. The change in these chemical groups can, among
other functions, allow for crosstalk between the ER and non-
genomic cell surface receptor signaling pathways.
36
The zinc-
containing DBD plays an important role in receptor dimeriza-
tion, allowing for binding of the ERs to DNA and positioning of
the ER to allow transcription of target genes and is the most
conserved between receptors (97%).
1,37
The hinge region con-
tains a large amount of variation within ERs (30% conserved) and
contains the signals for nuclear localization and post-translational
modications.
1
The C-terminal E/F domain is comprised of the
LBD and the ligand-dependent transcription activation function-
2 domain.
37
It is involved in ligand binding and plays a role in ER
dimerization. Differences in this domain are responsible for the
two splice variants ERb1andERb2(Figure 1).
In general terms, the ERs regulate the transcriptional activity of
target genes in response to E2 or to SERMs such as CC and TF
citrate.
33
The transcriptional mechanism of action of ERs begins
with the binding of E2 or of synthetic compounds to the
C-terminal E/F (ligand-binding) domain. This results in receptor
dimerization and binding to EREs on DNA, conformational
changes of the ER, and interaction with coregulators.
33
E2 also can
cause a rapid onset of action through the actions of the non-
genomic membrane-localized ER.
38
This leads to the activation
of different downstream signaling pathways, such as the mitogen-
activated protein kinases and phosphatidylinositol 3-kinase path-
ways, which in turn modulate cell proliferation and transcription.
39
ER Subtypes: ERaand ERb
The two ER subtypes in humans are ERaand ERb, localized
in the cytosolic and nuclear cellular compartments. These sub-
types are differentially expressed in different human tissues,
indicating tissue-specic functions.
40
Molecularly, the subtypes
are similar but with important functional differences. Although
ERbis smaller than ERa, they share a similar structure in the
DBD and LBD.
41
However, the AF-1 domains of ERaand ERb
differ signicantly, with varying lengths and amino acid
sequences.
35
This results in a distinct response of each subtype to
synthetic estrogen-like ligands such as TF and RAL.
35
These
compounds act as partial E2 agonists when interacting with ERa,
whereas they are pure E2 antagonists when interacting with
ERb,anding that could be attributed to differences in the
N-terminal regions encoding AF-1. These opposing responses of
ERaand ERbto the same compound are critically important to
remember when considering the administration of SERMs in
men, particularly with respect to their differential expression in
different organ systems.
Ligand-Receptor Interactions, Receptor Activation,
and Dimerization
Binding of E2 or synthetic estrogens or antiestrogens to the
LBD of the ER results in conformational changes of the ER with
concomitant dissociation from the heat shock proteins and
receptor dimerization. The heat shock proteins maintain the
receptor in the inactive state.
33
The conformational change and
dimerization result in homodimers (ERa:ERaor ERb:ERb)or
heterodimers (ERa:ERb). The extent to which homodimers or
heterodimers bind to DNA is directly inuenced by the relative
concentration of ERaand ERbwithin the specic cell type.
33
Those cells expressing the two subtypes have a unique set of
genes. The relative amounts of ER subtypes in a unique cell are
important determinants of that cells response to E2 or synthetic
ligands. The differential tissue effects have been instrumental in
the development of SERMs for the treatment of conditions of
breast cancer, osteoporosis, anovulation, and vaginal atrophy.
Then, these dimers bind to EREs on DNA.
EREs in the DNA
After dimerization of the ER, the ER-ligand complex binds
directly to the ERE, a specic DNA sequence, whereupon it
interacts with the transcriptional complex and coactivators and
ultimately results in activation of transcription.
42
The consensus
ERE, a 13-nucleotide segment with 10 nucleotides forming an
inverted repeat, is 50-GGTCAnnnTGACC-30, where n is any
nucleotide.
43
Other EREs have been demonstrated, all of which
consist of variations of the consensus sequence.
42
Differences in
at least one nucleotide of the consensus sequence can result in the
ERE being less responsive to the activated E2-ER complex. The
specic sequence of the response element affects the afnity that
a given receptor has for binding DNA. The consensus ERE was
rst identied from examination of DNA sequences in the
estrogen-regulated egg yolk precursor genes A1, A2, B1, and B2
from the African clawed frog.
44
ERabinds with greatest afnity
to the consensus ERE sequence found within egg yolk protein
(vitellogenin) gene A2 and less well to other imperfectEREs
within vitellogenin B1, ps2, and oxytocin genes.
45
This nding
illustrates how the sequence of the response element can be an
important determinant of the extent to which ERs activate gene
expression and their response to SERMs.
COACTIVATORS AND COREPRESSORS
Many positive and negative regulatory proteins known as
coregulators are recruited by the liganded and unliganded ER to
Sex Med Rev 2017;-:1e22
6Helo et al
carry out transcriptional functions.
46
Positive regulatory proteins
in this group are termed coactivators (histone acetyl and methyl
transferases); conversely, negative regulatory proteins are known
as corepressors (nuclear receptor corepressors 1 and 2). The
ER-ligand complex recruits coactivators to act as a transcriptional
activator. The ER coactivator recruitment site is composed of
residues within four protein helices in the ER.
47
Alternatively,
ER coregulators can be categorized according to mode of ac-
tion.
46
Thus, the two main categories of coregulators would
include those that covalently modify histones and those that
function dependently on adenosine triphosphate to modulate
promoter accessibility to transcription factors.
Recent evidence has shown that recruitment of coactivators
and corepressors to the ER and ER-ligand complex occurs in an
ordered, sequential fashion.
48
Activity of these coregulators is
cyclical or repetitive, permitting the cell to respond to changes in
levels of ER agonists or antagonists. The addition of side chains
to the E2 molecule backbone in SERMs results in steric clashes
within the protein helices interfering with coactivator binding.
The SERM-ER complex also can recruit its own complex of
specic cofactors different from the E2-ER complex.
30
Thus,
these processes might be an important determinant in the reac-
tion of specic cell types to synthetic ER ligands.
GENOMIC AND NON-GENOMIC ACTION OF THE ER
The genomic actionof ERs as described earlier is similar
among all steroid hormones and was described by the pioneering
work of Jensen and others.
49e51
This is the classic description of
ERs functioning as ligand-activated transcription factors, a process
that occurs after a time lag of at least 2 hours after E2 stimula-
tion.
52
In contrast to the genomic action of ERs, in recent years a
non-genomic process has been elucidated, wherein binding of E2
can have a demonstrable effect within seconds to minutes. This
effect is believed to be attributable to activation of plasma
membrane-bound receptors, resulting in different signal cascades,
such as activation of calcium- and calmodulin-dependent kinases,
release of intracellular calcium, or the mitogen-activated protein
kinases and phosphatidylinositol 3-kinase pathways.
52,53
At the
pharmacologic serum levels that are achieved by the SERMs,
32
there is a possibility of non-genomic action.
LOCATION OF ER IN THE MALE ANIMAL
When considering the anticipated effects of endogenous E2 or
synthetic non-hormonal compounds in the male animal, it is
critical to examine the location of ERs and the variable expres-
sion of ERaand ERbin different organ systems. Since the
discovery of ERbin 1996 by Kuiper et al,
40
the tissue distri-
bution of each ER subtype has been elucidated through different
animal models including mouse, rat, dog, cat, macaque,
marmoset, and human.
54e66
ERahas been shown to be preferentially distributed in the
brain and pituitary over ERbin mouse and rat models.
40,55
Many recent studies also have examined the distribution of
ERaand ERbin the male genitourinary tract. In general, ERb
has been shown to be preferentially expressed in the male
reproductive tract, with strong expression in the testis, epidid-
ymis, vas deferens, seminal vesicles, and prostate.
57e66
In addi-
tion, strong ERbexpression has been demonstrated in the corpus
cavernosum and spongiosum and throughout the urinary
tract.
59e62
In contrast, ERais expressed much more weakly in
the male genitourinary tract, with expression essentially limited
to efferent ductules and specic cell layers of the remainder of the
tract. Table 1 presents the full tissue distribution ndings
(location of ERs in male animals by subtype).
SERMS, MODULATORS OF THE ER
The rst SERM for clinical use was CC, which was patented
in 1959.
67
It was rst approved by the Food and Drug
Administration (FDA) in 1967 in women for the treatment of
ovarian syndrome and other anovulatory conditions in which
ovarian activity could be demonstrated by withdrawal bleeding
from progesterone. It has a long half-life and is readily
bioavailable.
68
It was soon recognized that SERMs exert antag-
onistic effects on estrogen, inducing the release of LH and FSH
and an increase in T in men.
69
SERMs have been used in
off-label treatment in men for the past 45 years despite the lack
of an FDA approval in men. More than 700 articles have
appeared in the peer-reviewed literature on the use of SERMs
(CC, TF, TOR, and RAL) in men for conditions ranging from
idiopathic infertility, hypogonadal infertility, HG, erectile
dysfunction, premature ejaculation, breast cancer, benign pros-
tatic hyperplasia, prostate cancer, gynecomastia, schizophrenia,
and osteoporosis.
CC AND INFERTILITY
Most studies on CC and infertility have attempted to address
whether SERMs have the ability to correct sperm parameter
anomalies and improve fertility. Most have been carried out in
men with eugonadism (EUG), specically excluding men with
HG. However, up to 41% of infertile men might have HG.
70e72
The scientic rationale for treating infertile men with EUG with
CC presumably has been based on the SERM-induced increase
in FSH and endogenous T production. Is it realistic to suggest
that an increase in LH, FSH, and T in the infertile man with
EUG will improve seminal parameters and pregnancy rates? This
paradox might explain in part why published studies investi-
gating the effect of SERMs on semen parameters and pregnancy
outcomes have produced such conicting results with respect to
fertility. What is incontrovertible is the impact of the SERMs on
endogenous T production in the man with normal or low normal
GTPs or secondary HG.
Early infertility studies were difcult to interpret because of
the lack of placebo (PCBO) controls, lack of adequate partner
evaluation, lack of randomization, inclusion of primary and
Sex Med Rev 2017;-:1e22
Cherchez La Femme7
secondary testicular failure, unclear or varying dosing regimens,
varying lengths of trials, small numbers of men, and early assay
methods. Early studies were done on normal men, but when
combined they provide a wealth of information.
The variability of response was demonstrated early. Jungck
et al
73
in an open-label therapeutic trial reported on 12 men with
normospermia and 28 with oligospermia on doses ranging from
25 to 100 mg/d for periods ranging from 4 to 10 weeks.
Increases, decreases, and no change in SC were seen in 17%,
33%, and 50% and 58%, 21%, and 21% in men with
normospermia and those with oligospermia, respectively. Mel-
linger and Thompson
74
reported increases (77%) and decreases
(23%) in 13 men with oligospermic EUG (by clinical obser-
vation) on CC (dose and duration were not reported). All men
with decreased SCs showed normalization after discontinuation
of CC. In a short open-label study, Mroueh et al
75
treated 15
men with severe oligospermic infertility (mean SC <7 million/
cm
3
) with CC 50 mg for 6 weeks with semen analysis 2 to
4 weeks after completion. The hormonal status of the men was
unknown and the short-term treatment of these men with severe
oligospermia showed no improvement in seminal parameters. No
adverse events (AEs) were reported. Clearly the period of
observation was too short to make any signicant conclusions.
Cargille et al
76
reported a 20% increase in LH and FSH in
three normal men treated with CC 200 mg for 5 days. The
increase peaked at 5 days and lasted for as long as 9 days after
discontinuation. T level increases paralleled the increases in LH.
Three normal men were suppressed with 9 days with
uoxymesterone, a potent oral anabolic steroid. None of the men
on uoxymesterone responded to CC. This suggested a
hypothalamic-pituitary mechanism of action of CC in men and
demonstrated that the blockade of the ER could be overcome by
the administration of sufcient T. The need for an intact
hypothalamic-pituitary axis was shown by Santen et al.
77
They found that men with congenital or acquired hypo-
gonadotropic HG did not respond to high or prolonged doses of
Table 1. Location and type of ER in mammals
Study
Receptor
type Organ or location Animal
Saunders et al
54
ERaEfferent ductules (epithelial cells), SV (stromal cells) Human, macaque,
marmoset
ERbTestis (Sertoli and Leydig cells), efferent ductules, epididymis,
vas deferens, seminal vesicles, bladder
Kuiper and Gustafsson
40
ERaEpididymis, testis, kidney, adrenal, prostate (stroma), bladder, liver,
thymus, brain, bone marrow, fat, lung
Mouse
ERbProstate (epithelium), bladder, liver, thymus, brain, bone marrow,
fat, lung
Nishihara et al
55
ERaPituitary Rat
Weihua et al
56
ERbProstate Rat
Makinen et al
57
ERbTestis Human
Lindner et al
58
ERbVascular endothelium Rat
Dietrich et al
59
ERaCorpus cavernosum and spongiosum (weak), urethral epithelium Human
ERbCorpus cavernosum and spongiosum (strong), urethral epithelium (weak) Human
Makela et al
60
ERbProstate, seminal vesicles, bladder, urethra Rat
Salmi et al
61
ERbProstate, urethra, bladder Rat
Jesmin et al
62
ERaCorpus cavernosum and spongiosum (weak), urethral epithelium (weak) Rat
ERbCorpus cavernosum and spongiosum (strong), urethral Rat
Epithelium (strong)
Zhou et al
63
ERaEfferent ductules Mouse
ERbTestis, epididymis, vas deferens Mouse
Nie et al
64
ERaTestis (interstitial cells and peritubular myoid cells), rete testis (epithelium),
efferent ductules
Dog
ERaTestis (interstitial cells), efferent ductules, epididymis (epithelial cells),
vas deferens
Cat
ERbRete testis (weak), efferent ductules (weak), epididymis (strong),
vas deferens (strong)
Dog, cat
Tsurusaki et al
65
ERaProstate (stromal cells of peripheral zone) Human
ERbProstate (stromal cells of peripheral zone and transitional zone) Human
Fixemer et al
66
ERbProstate (epithelium) Human
ER ¼estrogen receptor; SV ¼seminal vesicle.
Sex Med Rev 2017;-:1e22
8Helo et al
CC (50 mg twice daily), whereas normal men responded with a
125%, 42%, and 25% mean increase in LH, FSH, and T,
respectively. Similarly, Kulin et al
78
found that prepubertal boys,
before the maturation of their hypothalamic-pituitary axis, did
not respond to CC, providing further support that an intact and
functioning hypothalamic-pituitary-thyroid axis is necessary for
the mechanism of action of CC.
In a study on the impact of CC on pituitary secretion, Winters
et al
79
found that intravenous exogenous T and E2 up to two
times the physiologic secretion could not suppress the LH and
FSH increases induced by CC (100 mg twice daily). This is not
surprising considering the high serum levels achieved by oral
SERMs. One study found that with one 50-mg dose of CC, EC,
and ZU (molecular weight ¼405 g/mole), peak serum levels
were 400 to 800 ng/dL, roughly the same molar equivalent as
EUG serum levels of T and E2 (molecular weight ¼288 and
272 g/mole, respectively) that were achieved.
68
There appears to
be a threshold necessary to overcome the E2 blockade of CC.
The levels of exogenous T treatment that would overcome the
CC effect were not determined but the earlier work by Cargille
et al
76
demonstrated that is was possible.
Epstein and Clark (1977) examined 16 men with idiopathic
oligozoospermia (OS; SC 10 million/cm
3
) and infertility
(duration ¼3e13 years) who were treated with open-label CC
100 mg three times a week for a minimum of 4 months. Ten of
16 men had T testing and half had baseline randomT levels
lower than 300 ng/dL. Sixty-two percent of men responded with
a signicant increase in SC or a pregnancy. The magnitude of the
T response to CC did not affect the response rate. Men who did
not respond had a lower baseline SC (6.8 vs 12.5 million/cm
3
)
and four of the six had a paradoxical decrease from their baseline
T level.
In the rst PCBO-controlled, double-blinded, crossover study
by Ronnberg,
80
CC 50 mg/d was administered to the treatment
group for 3 months followed by a 3-month washout for 27 men
with EUG (T ¼518 ng/dL) and eugonadotropic infertility. OS
was not an inclusion criterion (SC ¼17 million/cm
3
). Although
the investigator noted a 116% increase in SC, no changes in
sperm motility (MOT) or percentage of normal sperm
morphology (MORPH) were found. Men who started with a SC
lower than 10 million/cm
3
did not appear to derive as much
benet from the CC. Despite a 4-year average period of infer-
tility, three pregnancies were reported in the CC group compared
with one in the PCBO group. Signicant increases in FSH, LH,
and T (T >1,000 ng/dL) were seen in the CC group, despite
normal baseline T levels. The short duration of this study, small
numbers, and the confounding variable of the crossover design
make the results difcult to interpret with respect to seminal
parameters.
Wang et al
81
was the rst to compare CC with exogenous T
therapy in their randomized PCBO-controlled study of 46 men
with EUG (T ¼576 ng/dL) and idiopathic OS (SC <20
million/cm
3
) assigned to PCBO (6 men), CC 25 mg/d (11 men)
or 50 mg/d (18 men), mesterolone 50 mg twice a day (12 men),
pentoxifylline 400 mg three times a day (11 men), or T enan-
thate 100 mg (6 men) or 200 mg (9 men) intramuscularly every
2 weeks. Patients were treated for 6 to 9 months, with sperm
parameters and hormone changes as their primary end points. SC
increased 115% in the CC group (P<.05), yet at the end of 6
months men still had OS (15.3 million/cm
3
). In contrast, men in
the higher-dose T enanthate group showed a decrease in SC
without a rebound increase in SC after discontinuation of ther-
apy. The CC groups showed an increase in FSH and T. Those in
the CC 25 mg/d group showed a greater increase in T (1,380 vs
1,046 ng/dL), whereas those in the 50 mg/d group showed a
greater increase in FSH to (25.2 vs 10 mIU/mL) with compa-
rable LH levels (15.7 vs 15.5 mIU/mL). Eight pregnancies
occurred in the CC group, 75% of which had an SC higher than
10 million/cm
3
at baseline. No pregnancies occurred in the other
treatment groups.
81
Micic and Dotlic
82
reported their ndings of a randomized,
open-label, non-treatment comparator study of 101 infertile men
(>2 years) with idiopathic eugonadotropic (FSH) OS (SC ¼8
million/cm
3
) treated with CC 50 mg/d (56 men) or no treatment
(45 men) for 6 to 9 months. Unlike previous studies in men with
an average SC lower than 10 million, SC on treatment increased
to 16 million and seven pregnancies ensued, with no pregnancies
in the untreated group. Overall, mean SC did not increase in the
non-treatment group. Eighteen vs three men achieved an SC
higher than 20 million/cm
3
in the treatment vs no-treatment
group, respectively. LH and T levels were not reported. No
men reported any side effects and libido and sexual performance
were not altered, although no specic patient-reported outcome
(PRO) measurements were used. There were no reports of
gynecomastia.
Sokol et al
83
similarly reported no change in sperm parameters
in their randomized, double-blinded, PCBO-controlled study of
23 men with EUG (T ¼544 ng/dL) and idiopathic OS (SC ¼
17 million/cm
3
). Patients were randomized to CC 25 mg/d or
PCBO for 12 months. End points included SC, hormonal pro-
les, PR, hamster sperm penetration assay (SPA), and
gonadotropin-releasing hormone stimulation. Patients in the
active treatment arm showed an increase in LH, FSH, T, and E2,
but the PR was higher in the PCBO group (44.4%) compared
with the CC group (9.1%). Gonadotropin-releasing hormone
stimulation on CC was greater in the treatment group, supporting
the hypothalamic mechanism of action of CC. Although the
study was well randomized and PCBO controlled, the small
numbers did not preclude but did cast some doubt on the utility
of CC in the treatment of idiopathic EUG oligospermic infer-
tility. Chan et al
84
reported that CC did not have a detrimental
impact on SPA, an interesting observation considering the pres-
ence of ERs in sperm. The impact of the use of CC on human
intracytoplasmic sperm injection has never been reported.
The World Health Organization published an international
multicenter (11 sites), randomized, double-blinded study of 141
Sex Med Rev 2017;-:1e22
Cherchez La Femme9
men with EUG (T ¼478 ng/dL) and infertility (36 months)
with idiopathic oligo-asthenozoospermia (OAT; SC <7 million/
cm
3
, MOT ¼26) receiving CC 25 mg/d vs PCBO for 6 months
with up to 3-month follow-up after the end of treatment.
The investigators reported no difference in pregnancy rates
(CC ¼9.7% vs 7.9%) or sperm quality in this cohort of men,
85% of whom presented with primary infertility. Discontinua-
tion was high (CC ¼24% vs 37%), weakening the statistical
power of the study.
85
Although they failed to demonstrate an
effect on semen quality or pregnancy rates, they did report a
signicant increase in LH, FSH, and T in the CC group. Side
effects resulting in dropouts included visual disturbances, dizzi-
ness, and headaches on CC (two men) and sexual impotence and
lethargy on PCBO (two men). Because many studies have shown
decreased efcacy with an SC lower than 10 million, the lack of
benet might be related to the severity of the oligospermia at
baseline. Nonetheless, this study underscored the need for
PCBO-controlled studies when pregnancy rates are used as an
outcome.
Hussein et al
86
reported on a prospective open-label study of
42 men with idiopathic non-obstructive azoospermia (AZO) on
CC therapy for 3 to 9 months (mean ¼5.15 months); this was
one of the rst studies to include men with HG, with 42.9% of
patients demonstrating a baseline T lower than 300 ng/dL.
Unique to this study, CC dosing was titrated such that serum T
was 600 to 800 ng/dL and nearly all patients underwent initial
testicular biopsy examination before initiation of treatment with
CC. At 6 months, 15 patients (35.7%) still had AZO and
underwent testicular sperm extraction. All patients with post-
treatment AZO had sufcient sperm for extraction by
intracytoplasmic sperm injection but pregnancy rates were not
reported. The nding of post-treatment sperm in the ejaculate
was highly correlated to the initial testis histologic pattern, with
hypospermatogenesis and maturation arrest at the level of sper-
matids being more favorable than maturation arrest at the level of
spermatocytes. A longer exposure to CC resulted in a better
chance of sperm in the ejaculate. The investigators concluded
that CC therapy could be of benet to patients with non-
obstructive AZO before surgical extraction of sperm for intra-
cytoplasmic sperm injection.
Helo et al
87
in randomized double-blinded study comparing
CC 25 md/d with the aromatase inhibitor, anastrozole (AZ) 1
mg/d, in 26 men with HG (T ¼248 ng/dL), obesity (body mass
index ¼32 kg/m
2
), and infertility (>1 year) found that hormone
levels (AZ T ¼408 ng/dL, CC T ¼571 ng/dL) improved in the
two groups. The T differences were statistically signicant at
6 and 12 weeks. T/estradiol ratios were signicantly better on
treatment in the AZ group. Because the primary end point was
change in T, OS was not an inclusion criterion (SC ¼33
million/cm
3
) and no changes in SC were seen. During the 3-
month study, three pregnancies occurred (11.5%). PROs
demonstrated no changes. The Androgen Deciency in the
Aging Male (ADAM) score, Erection Hardness Score, and the
International Index of Erectile Function (IIEF) score showed no
change. It has been recently suggested that estrogen is important
in sexual male sexual function
88
; the lack of any change in the
PROs despite the lowering of E2 levels with AZ and ER blockade
with CC is worth noting despite the short-term nature of the
study and small numbers and the study was not powered for the
PRO end points.
Studies have examined the benets of combined CC therapy
or compared with antioxidants.
Abel et al
89
in a multi-institutional study randomized 179
men with EUG (T ¼576 ng/dL) idiopathic infertility (SC ¼30
million/cm
3
) to vitamin C (VC) 200 mg/d (86 men) or CC 50
mg/d (93 men) for 6 months of treatment with an additional 3
months of follow-up. They found no difference in pregnancy
rates (CC ¼17% vs VC ¼13%) or semen parameters (not
reported) and on subgroup analysis failed to demonstrate that
FSH or baseline SC could be used to predict the response to
therapy. Hormone parameters were reported as signicantly
increased only in the CC cohort but only the FSH increases were
reported. Limitations of this study included lack of sufcient
statistical power for all the end points, loss to follow-up in 21%
of patients, and nearly 50% of couples had incomplete or
abnormal fertility testing results in the wife. Six patients on CC
complained of headache on CC, which resulted in one dropout.
Ghanem et al
90
reported on a randomized, double-blinded,
PCBO-controlled study of 60 infertile men (4.5 years) with
OS (SC <11 million/cm
3
, MOT <33%) treated with com-
bined CC 25 mg/d and vitamin E 400 mg/d (30 men) or PCBO
(30 men) for 6 months. Baseline T was measured but not re-
ported and apparently not exclusionary. Men with an increased
FSH were excluded. Very little information was reported on
baseline characteristics. Pregnancy rates were 36.7% (seven) vs
3.3% (one) in the CC vs PCBO group, respectively. SC (18
million/cm
3
) signicantly improved in the CC group.
Moradi et al
91
in a randomized, open-label, parallel-arm trial
studied 52 men with idiopathic OAT (SC ¼20 million/cm
3
,
MORPH ¼45%, MOT ¼24%) and infertility (2.98 years).
Men received CC 25 mg/d (20 men) or L-carnitine 2 g/d (32
men) for 3 months. In addition to excluding men with HG, the
investigators excluded men with an SC lower than 10 million/
cm
3
.Theyreportedsignicantly increased SC, MORPH, and
MOT in the CC group and L-carnitine cohort (SC ¼42 million/
cm
3
,MORPH¼58%, MOT ¼43%). It is difcult to draw
conclusions from their results given the lack of a PCBO group, the
paucity of reported data, and the short duration of study.
ElSheikh et al
92
reported similar ndings in their randomized,
prospective, open-label study of 90 men with EUG (not dened)
and idiopathic OAT (SC <8 million/cm
3
, MOT <24%). They
compared CC 25 mg/d, vitamin E 400 mg/d, and CC plus
vitamin E therapy for 6 months. They failed to report baseline
hormone levels. A signicant improvement in SC (12.65
million/cm
3
) and MOT (40.5%) was seen, but patients still had
Sex Med Rev 2017;-:1e22
10 Helo et al
oligospermia. As in the previous study, clinical interpretation of
results is limited by the lack of a PCBO group and lack of
baseline demographic and pregnancy data.
TF AND INFERTILITY
TF, another SERM, is the trans-stereoisomer of a triphenyl-
ethylene with largely antiestrogenic properties and has been used
and studied extensively in the treatment of breast cancer.
93
Willis et al
94
examined the hormonal effects of TF (10 mg/d for
6 months) in a PCBO-controlled, single-blinded, crossover study
of nine infertile men with EUG (T ¼745 ng/dL) and oligo-
spermia (SC <30 million/cm
3
). Concentrations of serum LH and
FSH increased signicantly after 6 and 4 months, respectively.
T increased to 1,095 ng/dL after 4 months of treatment and
serum E2 increased from 50 to 172 pg/mL by 6 months. The
response to TF was rapid, with T and E2 levels increasing
signicantly by day 4 of treatment, despite no signicant changes
in GTP. Baseline SC varied tremendously (mean SC ¼10.6
million/cm
3
,medianSC¼1.7 million/cm
3
). No patients with a
baseline SC lower than 10 million/cm
3
(ve of nine) increased
their SC, whereas uctuating increases were seen in men with
baseline SC higher than 10 million (four of nine). As part of the
protocol, men were challenged intermittently with luteinizing-
releasing hormone (LHRH) while on treatment. Although the
LHRH challenge did not change GTP secretion with short-term
TF treatment (7 days), long-term treatment (>3 months) resul-
ted enhancement of LH and FSH secretion, suggesting a hypo-
thalamic vs pituitary effect in long-term TF therapy. This is
consistent with the study by Hashimoto et al
95
;menwith
hypothalamic hypogonadotropic HG with no response to CC but
responses to the LHRH challenges resulted in an increase in LH
and FSH. Very little baseline demographic information was
provided in the study.
Vermuellen and Comhaire
96
treated 21 men with idiopathic
OS (28 years old, SC ¼14.7 million/cm
3
,T¼605 ng/dL) for 6
to 9 months with TF 20 mg and found a signicant increase in
GTP, T, and E2 levels. A signicant increase in SC was observed
only in subjects with an SC lower than 20 million/cm
3
(15 men)
and normal basal FSH levels (20 men). When basal FSH levels
were increased (one man) or the SC was higher than 20 million/
cm
3
(six men), no effect on sperm density was seen. MOT was
not improved by TF treatment. The small numbers in the study
hamper the statistical and clinical signicance of the SC changes.
Bartsch and Scheiber
97
studied the of effect of 12 months of
daily open-label TF 30 mg administration on semen analysis,
hormonal prole, and pregnancy rates of men with EUG OS
(46 men, T ¼480 ng/dL, LH ¼9.2 mU/mL, FSH ¼5.9 mU/
mL) and men with hypergonadotropic OS (10 men, LH ¼20.3
mU/mL, FSH ¼20.1 mU/mL; mean SC ¼10.3 million/cm
3
).
Although infertility was implied, no period of infertility was
reported. Thirty-eight of 56 patients (67%) responded as dened
by an SC higher than 20 million/cm
3
. An overall pregnancy rate
of 23% was reported during the study. Hormone levels were not
uniformly assessed in all men and there was no PCBO arm. The
emphasis of the results was on the responders vs non-responders,
which included men with HG. A surprising nding of the study
was that the hypergonadotropic men had a 60% response rate;
unfortunately, hormone levels and GTP levels were not reported.
The investigators did not address why men with highly increased
GTP, suggestive of primary testicular failure, would respond to
TF therapy.
Traub and Thompson
98
studied 46 men with longstanding
infertilitywith open-label TF 20 mg/d for 6 months. T and LH
levels were reported as normaland FSH was signicantly
increased in four men, although specic levels were not reported.
All men with increased FSH responded with at least a doubling
of their count and nine (21%) pregnancies. The improvement in
SC was most apparent in the group with an SC lower than 5
million/cm
3
(10 men), with four pregnancies occurring in this
latter group. None of the azoospermic men (four men) respon-
ded to TF. Of signicance was the reporting of side effects in
seven patients (16%). A severe loss of libido was seen in four
men, two of whom discontinued therapy and two continued
with a return of libido while on therapy. Two men complained
of disturbing hair loss and one of weight gain while on the study.
The lack of a PCBO group, lack of reported data, small numbers,
and the heterogeneous nature of the men studied make the re-
sults difcult to interpret.
Danner et al
99
in a 6-month open-label study of TF 20 mg/d
of 15 men, 12 with EUG OS and 3 with hypergonadotropic OS
(mean SC not reported, T not reported) demonstrated a signif-
icant increase in sperm density in 75% (12 men). Unlike the
study by Traub and Thompson, men with hypergonadotropic
OS showed no increase in sperm density despite increase in GTP
and T. There were no treatment-emergent side effects with
respect to libido, development of gynecomastia, or nipple pains.
The lack of a PCBO group, paucity of reported data, and small
numbers weaken the strength of the conclusions.
Buvat et al
100
studied 25 infertile men (>2 years) presenting
with eugonadal (T >400 ng/dL) and eugonadotropic oligo-
spermia (SC ¼12.8 million/cm
3
) in an open-label trial of TF
(20 mg/d) for 4 to 12 months with semen analyses before TF and
at 3 and 12 months; 14 were followed with hormone testing
before TF and after 2 and 12 weeks of TF. Although semen
volume, MOT, and MORPH were unaffected by TF, a twofold
increase of the mean SC (28 million/cm
3
) was seen. Mean values
of T, LH, and FSH increased during treatment, but the differ-
ence was signicant only for T and FSH; actual numbers were
reported only graphically. Ten pregnancies (40% of cases) were
reported during a 161-month period of observation. Whether
the pregnancies occurred during or after treatment or when the
pregnancies occurred was not reported.
Torok
101
reported on his results of a randomized 3-month
study of men with oligospermia (SC <40 million/cm
3
)and
infertility (2 years) with TF 20 mg vs PCBO. SC increased in the
Sex Med Rev 2017;-:1e22
Cherchez La Femme11
two groups, whereas MOT and MORPH demonstrated no
difference. Pregnancy, dened as having occurred within a year of
starting treatment, was roughly equal in the treatment and PCBO
groups (25% and 33%). Neither GTPs nor T levels were
measured.
Early studies performed in men with EUG idiopathic OS
showed improvement in hormone levels but a marginal change in
semen parameters. AinMelk et al
102
performed a small PCBO-
controlled, double-blinded, crossover study of 16 men with
EUG (T not reported) OAT (SC ¼17 million/cm
3
,
MOT ¼32%) using TF 20 mg/d for 6 months. Semen analysis
was done at 3, 6, 9, and 12 months. LHRH stimulation was done
at baseline and at 6 months in all men and SPA was performed at
the same interval in seven men. Statistically signicant increases vs
PCBO were seen in GTP and T but not in SC (17.68 vs 18.4
million/cm
3
) or MOT (32% vs 35%) or SPA. LHRH stimulation
favored the TF group but the small numbers precluded statistical
signicance. Two pregnancies, unlikely related to treatment,
occurred in the TF group within 1 month of starting TF. The
study was too small and insufciently powered to address all the
measured outcomes statistically. No AEs were reported.
Krause et al
103
reported on a randomized, double-blinded,
parallel-arm, PCBO-controlled bi-institutional study of 76 men
with EUG (T >490 ng/dL), infertility (26.5 months), and OS
(mean SC ¼9 million/cm
3
) on TF 30 mg (39 men) for
3 months. Although T increased dramatically (790 ng/dL), levels
of LH, FSH, and SC (9.3e11.4) did not change signicantly vs
PCBO. Pregnancy rates in the TF and PCBO groups were
13.5% and 7.6%, respectively, at 1 to 7 months after starting
therapy and the differences were not statistically signicant. The
investigators did not explain the lack of signicant increase in
GTP in light of the T response.
Kotoulas et al
104
studied 239 men with OS or EUG OAT and
infertility (SC <20 million/cm
3
) in a randomized, double-
blinded, parallel-arm, PCBO-controlled (117 men) study of
TF 20 mg (122 men). T or GTP levels before and after treat-
ment were not reported and 48 men on TF were normospermic
with asthenozoospermia only. The number of men who were
normospermic with asthenozoospermia on PCBO was not re-
ported. Confusingly, seminal parameters were assessed 3 months
after cessation of therapy. The investigators reported a signicant
improvement in SC in the men with OS. SC was improved in
49% vs 20.5% in the TF vs PCBO group. MOT and MORPH
were not signicantly affected. AEs were not reported.
Adamopoulos et al
105
compared TF with T undecanoate (TU)
in a randomized PCBO-controlled study of 80 men with EUG
(not dened) and idiopathic OS (total SC <40 million).
106
The
blinding was uncertain. Patients were randomized to PCBO
(18 men), TU 40 mg three times daily (20 men), TF 20 mg/d
(19 men), or TU plus TF for 6 months. The rationale for com-
bined treatment was the theoretical detrimental effect of the
SERM on epididymal function. Patients receiving TF or TF plus
TU therapy showed an increase in FSH. All active treatment arms
showed an increase in serum T from baseline, with the greatest
increase in the TF plus TU group (591 vs 850 ng/dL, respec-
tively). Total SC, but not MOT, improved signicantly from
baseline in all groups except the PCBO group, with what appeared
to be an additive effect of combination therapy.
106
Unfortunately,
FSH and T levels in the TU-alone arm were not reported. With a
wealth of data demonstrating the deleterious effects of exogenous
Tonspermatogenesis,
107
one can only assume that the TU
T levels were subtherapeutic. Reporting the GTP data would have
claried this point.
In a follow-up to their previous study, Adamopoulos et al
105
performed a randomized PCBO-controlled study of 212 men
with OS (SC <10 million/cm
3
) and EUG (T >500ng/dL)
treated with TF 20 mg/d and TU 40 mg three times daily or
PCBO for 6 months. They were compared with 82 untreated
men with EUG normospermia (SC ¼45.7 million/cm
3
).
TF-only and TU-only cohorts were not included because of the
previous inferiorresults to combined therapy. Hormones and
GTP were not collected during the study. At 6 months, the
reported pregnancy rates in the TF plus TU, PCBO, and un-
treated groups were 26.4%, 8.7%, and 26.4%, respectively.
However, the pregnancy data were incomplete, being available in
83% of the two treatment arms and in 69% of the untreated
group. At 6 months, the treatment arm demonstrated improved
SC (SC ¼7.9 vs 16.4 million/cm
3
, MOT ¼38.5 vs 41.6%,
MORPH ¼50.2 vs 56.6%). As in the previous study, the exact
contribution of the TU to the results remains unclear.
Guo et al
108
reported on 120 men with EUG (T not reported)
OAT (SC <11million/cm
3
, MOT <20%) in an open-label
parallel-arm study of TF 20 mg/d or indomethacin 25 mg
twice daily for 3 months. Sperm MOT improved from baseline
in the two groups, but total sperm count and concentration,
although still oligospermic, improved only in the TF group
(SC ¼10.24 vs 14.67 million/cm
3
, MOT ¼19.2% vs 24.7%).
The investigators also evaluated various oxidative stress parame-
ters and noted that although parameters improved in the two
groups, improvement was greater in the TF group. A PCBO
group would have been useful.
THE OTHER SERMS: TOR AND RAL
The structure of TOR differs from that of TF in that a chlorine
atom replaces one of the hydrogen atoms in the ethyl side chain. It
has been FDA approved for the treatment of breast cancer and has
been investigated to counter the decreased bone mineral density
changes of androgen deprivation therapy (Figure 2). Its efcacy
and side effect prole are very similar to those of TF.
109
RAL is
indicated for the treatment and prevention of osteoporosis in
postmenopausal women and the treatment of breast cancer. It
appears to act as an estrogen agonist in decreasing bone resorption
and bone turnover. The result is increased bone mineral density
and a decreased fracture incidence. In uterine and breast tissues, it
acts as an estrogen antagonist.
Sex Med Rev 2017;-:1e22
12 Helo et al
Farmakiotis et al
110
published their prospective single-arm
open-label interventional study of 100 men with EUG
(T >485 ng/dL) idiopathic OS (SC <30 million/cm
3
) and
infertility (>1 year) who were treated with the SERM TOR
60 mg/d for 3 months. Similar to studies with CC and TF, FSH
and serum T increased signicantly. Seminal parameter data were
stratied by those who achieved a pregnancy and those who did
not. Extrapolating the data, 44%, 9%, and 28% improvements
were seen in SC, sperm MOT, and sperm MORPH, respec-
tively, for the entire cohort. The statistical signicance of these
changes was not reported. Starting mean SC was above the
World Health Organization threshold for infertility at 27
million/cm
3
. Twenty-two couples were able to achieve pregnancy
within 2 months of the end of treatment. A post hoc analysis
showed that SC per ejaculation and percentage of spermatozoa
with normal MORPH were prognostic indicators for the
achievement of pregnancy. Unfortunately, there was no PCBO
group.
Tsourdi et al
111
over a 3-year period consecutively assigned
284 men with EUG (T >490 ng/dL) and idiopathic OS (SC
<32 million/cm
3
) to TF 20 mg/d, TOR 60 mg/d, or RAL 60
mg/d for 3 months. Men in the TF and TOR groups showed a
statistically signicant increase in FSH compared with the RAL
group. Although the TF and TOR groups also showed an in-
crease in serum T from baseline, T levels in the RAL group
remained essentially unchanged at 3 months. Given the estrogen
agonistic properties of RAL, this nding is not entirely surpris-
ing. Despite these differences in hormonal effects, all three
SERMs improved sperm concentration and normal MORPH,
but it should be noted that SC at baseline was greater than 20
10
6
/mL in all groups.
Two studies have been undertaken with RAL in elderly men
investigating the effects of RAL on T and bone turnover markers.
Doran et al
112
in a randomized, double-blinded, PCBO-
controlled, 3-month study of RAL 60 mg/d in 50 healthy elderly
men (69.8 years old) with EUG (T ¼369 ng/dL) demonstrated
a nominal increase in T (67 ng/dL) with a statistically signicant
change only in FSH. RAL had no signicant effect on bone
turnover markers or lipid levels. No serious AEs were reported
and there were no dropouts because of side effects. Reported side
effects with RAL vs PCBO were hot ushes, nipple tenderness,
worsening libido, erectile dysfunction, and prostate symptoms in
four vs none, two vs two, three vs two, two vs one, and two vs
three, respectively. Duschek et al
113
undertook a randomized,
double-blinded, PCBO-controlled, 3-month study of RAL
120 mg/d in health elderly men (63.1 years old) with EUG
(T ¼493 ngl/dL), looking at serum lipids, pituitary-gonadal
axis, prostate markers, and bone turnover. Signicant increases
in T (579 ng/dL), LH, FSH, E2, and prostate-specic antigen
(0.2 mg/L, 17%) were seen with no changes in serum phosphate,
alkaline phosphatase, or the fasting urine calcium/creatinine and
urinary hydroxyproline/creatinine ratios and decreases in total
cholesterol. Like the previously described study, there were no
serious AEs or dropouts. No decrease in libido or erectile
dysfunction was reported.
DO NO HARM. ALL NEWS IS NOT GOOD
The possibility of the estrogenic and antiestrogenic properties of
CC and the differential biologic activity of the stereoisomers were
extensively reviewed by Clark and Markaverich.
114
In selected
individuals, SERMs could have a benecial effect and a detri-
mental effect in others. Animal and human data were analyzed
and the interested reader is encouraged to review the article. In
their words, The actions of clomiphene must be assessed is each
species, organ tissue and cell type on an individual basis.
114
The possibility of testicular toxicity was suggested by Heller
et al
115
in a highly unique study. They exposed 14 healthy men
with normospermia (>30 million/cm
3
) and EUG to varying
daily doses of CC for 2 to 12 months (50 mg in 5, 100 mg in 1,
200 mg in 6, and 400 mg in 2). In addition to hormonal assays,
testicular biopsies were performed before and after treatment.
Ophthalmologic examinations were performed at regular in-
tervals. Four of ve men on 50 mg had signicant increases,
whereas ve of seven on doses of 100 to 400 mg had signicant
decreases, in SC. SC decreased below 1 million/cm
3
in the two
men on 400 mg but rebounded after discontinuation. The his-
tologic changes are poorly described but all men had evidence of
slighttubular hyalinization and decreased tubular lamina, with
a 30% to 60% increase in damagedspermatids in those whose
SC decreased. Follow-up biopsies after discontinuation of ther-
apy showed normalization of the histology. Urinary GTPs and
steroids increased in all dosage groups. All ophthalmologic ex-
aminations were normal and no signicant AEs were reported
despite the high doses.
Shanis et al
116
published a case-control study comparing 144
patients with subnormal motile densityon CC 25 mg/d or
every other day for a varying duration (range ¼1e18 months)
with a control group with normal semen parameters. They re-
ported a signicant decrease in the MORPH, yet they failed to
report baseline or follow-up hormone levels or SC and their
control group had a signicantly larger number of normal sperm
forms at baseline. The study was not randomized and poorly
standardized, making the results of questionable signicance.
Parinaud et al
117
evaluated the effects of CC on fertile donor
spermatozoa by analyzing semen samples from 12 fertile donors.
They found that incubation of spermatozoa with CC increased
the percentage of acrosome-reacted spermatozoa, but with
impaired MOT and viability, raising concerns that CC could
have harmful effects on spermatozoa.
SUMMARY
There is ample evidence supporting the use of SERMs in male
infertility. Studies have uniformly conrmed the ability of
SERMs to improve serum T, LH, and FSH in men with EUG
Sex Med Rev 2017;-:1e22
Cherchez La Femme13
and infertility, with conicting results with respect to seminal
parameters and pregnancy rates. The conicting results are a
reection of the different inclusion and exclusion criteria, study
designs, study durations, lack of PCBO arms, dosages used, end
points evaluated, and frequently the lack of statistical power for
the end points. Although some studies have reported improved
semen parameters in patients on SERMs, others have failed to
show a statistically signicant effect, with a handful of studies
suggesting a deleterious effect on spermatogenesis or sperm
quality. The optimal role for SERMs has yet to be determined.
There is a paucity of data with SERMs in men with HG, EUG,
and infertility. SERMs might work best in the management of
the man with HG and infertility or the man with symptomatic
HG who warrants treatment of his symptoms but who desires to
maintain his fertility. Clinicians should consider SERMs as
treatment for selected infertile men with the caveat that, despite
proven efcacy, it remains an off-label use of a medication.
Appropriate patient counseling, informed consent, and shared
decision making should always be undertaken. Optimal dosing
schedules and duration of treatment have yet to be determined
and although long-term safety data are not available, despite the
long-term exposure of infertile men to SERMs, no major safety
issues have arisen.
SERMS AND HYPOGONADISM
Guay et al
118
were the rst to report on a randomized, PCBO-
controlled, double-blinded, crossover study of 17 men (60.5
years old) who presented with erectile dysfunction conrmed by
nocturnal penile tumescence testing and diagnosed with
secondary HG (T <250 ng/dL). Secondary HG was conrmed
by LHRH and CC challenges before entry. Patients were treated
with CC 50 mg or PCBO three times a week for 8 weeks,
followed by a 2-week washout period and then treatment with
the other regimen for 8 weeks. At 8 weeks, patient treated with
CC showed a 122% increase in serum T, a 59% increase in LH,
and a 65% increase in FSH. At rst glance, no signicant
changes in sexual questionnaire responses or nocturnal tumes-
cence parameter were seen. In a subgroup analysis by age
(mean ¼53 vs 66 years), statistically signicant improvements
were seen in nocturnal penile tumescence and sexual question-
naires responses in the younger group. It is not surprising that
the older cohort might not manifest improvement; they were
more likely to have sexual dysfunctions from disease processes
other than HG (ie, vascular disease). Furthermore, the study
might not have been sufciently powered for the nocturnal
penile tumescence and sexual dysfunction outcomes.
Guay et al
119
retrospectively reviewed charts of 178 men with
hypogonadotropic HG (T not reported) and erectile dysfunction,
dened as the inability to achieve or maintain an erection long
enough to complete sexual intercourse satisfactorily in more than
50% of attempts. They were treated with CC 50 mg three times
a week for 4 months. The primary end point was a home log of
sexual encounters. Men had to record the number of sexual
encounters and whether they resulted in successful sexual inter-
course. A successful response was dened as the ability to com-
plete intercourse in more than 75% of attempts; a partial
response was dened as successful intercourse in 50% to 75% of
attempts. The men with a failed response did not notice any
change in their sexual activity. This study predated the IIEF and
current Sexual Encounter Proles commonly used in erectile
dysfunction research. There was no PCBO group. Mean age was
54.3 years Almost 39% of men were responders, 36.4% were
partial responders, and 24.8% were non-responders. As in their
previous study, improvement in sexual symptoms correlated with
improvement in T levels. Free T levels increased more often in
patients who were responders (9.3e21.2 pg/mL) compared with
non-responders (9.8e17.6 pg/mL). The increased aged and
medical comorbidities negatively affected response rates. No AEs
were reported.
Shabsigh et al
120
reported the results of a short-term open-
label interventional study of 36 healthy patients with HG
(T ¼246 ng/dL) who were treated with CC 25 mg/d for 4 to 6
weeks. Because only three patients were obese, this does not
represent a typical population with HG. Total T increased to
610 ng/dL with a 43% increase in E2 (mean ¼32.3e43.3 pg/
dL). Normal E2 levels are 22 to 55 pg/dL. Sub-analysis of men
younger than or older than 40 years demonstrated comparable
changes in T levels. No AEs were reported in this short-term
study. Symptom improvement was not assessed.
Taylor and Levine
121
reported on a retrospective comparative
study of 104 men with HG (T ¼277 ng/dL) with or without
infertility who were placed on CC 50 mg/d or T gel with an
average follow-up of 23 months. The primary end points were
cost, T levels, and the sexual function domain of the ADAM
questionnaire. Average post-treatment T was comparable in the
two groups (CC ¼573 vs T gel ¼553 ng/dL). The monthly
cost of T gel was roughly four times that of CC ($274 vs $83).
The two treatments resulted in signicant improvements in
sexual function. There were no signicant prostate-specic an-
tigen or hematocrit changes and no AEs were reported on CC.
Moskovic et al
122
reported on the safety and efcacy at 3 years
in their retrospective study of 29 men with HG (T ¼288 ng/dL,
44 years old). They were started on CC 25 mg every other day
and were titrated to a target total T level of 550 ng/dL. At 3 years
T increased (T ¼582 ng/dL) with no apparent tachyphylaxis. Of
46 men who started CC, 29 (75%) remained on therapy at 36
months. There was no PCBO for comparison in this
study. ADAM scores initially decreased, but then increased
signicantly at last follow-up, possibly reecting attrition of the
non-respondersat the 3-year follow-up. Bone densitometry
showed a remarkably high baseline osteoporosis-osteopenia rate
(72%), which improved to 50% at 1 year and remained stable
thereafter. No other study has reported such a high baseline
prevalence of osteopenia or osteoporosis in men with HG or such
a dramatic improvement in bone density on CC. Sufce it to say
no decrease in bone densitometry was seen, a potential concern
Sex Med Rev 2017;-:1e22
14 Helo et al
with long-term antagonism of the ER and the importance of
estrogen in the maintenance of bone density.
Mazzola et al
123
sought to determine predictors of biochemical
response in 76 men with HG (T ¼179 ng/dL, 46 years old)
followed for at least 6 months (mean ¼7.8 months) on CC
25 mg every other day in a non-randomized, retrospective, and
open-label study. Indications for treatment were heterogeneous
(infertility and symptoms of HG). The relatively youthful
population is not typical of treatment for secondary HG.
Biochemical response was arbitrarily dened as a T increase
greater than 200 ng/dL or greater than 400 ng/dL. Forty-four
men (57%) were up-titrated to 50 mg/d at 6 months if they
did not respond. Sixty-four percent of patients met the criteria
for response, although the dose to which they responded was not
clear. On linear regression, the only predictors of biochemical
response to CC were testicular volume (Prader orchidometer)
larger than 14 mL or LH lower than 6 IU/mL. Symptom relief
was not assessed. No side effects of gynecomastia, nipple
tenderness, or decreased libido were reported. Further study is
needed before the results can be generalized.
Ramasamy et al
124
compared CC with exogenous T in their
retrospective cross-sectional study of 93 patients. They compared
31 patients on CC, 31 on T injections, and 31 on T gels. Serum
T increased in all groups, although patients on T injections
showed a twofold increase in T compared with CC or T gel
(1,104 vs 504 vs 412 ng/dL, respectively). Patient in the CC and
T gel groups showed a comparable increase in serum T and all
groups had similar quantitative ADAM scores, indicating that
there might be a threshold limit above which little symptomatic
benet can be derived. Men on T injections reported greater
libido based on quantitative ADAM scores than men in the other
groups, but the investigators did not report pretreatment quan-
titative ADAM scores.
The prevalence of obesity has increased dramatically
throughout all ages. HG is associated with obesity, although the
causal relation has not been established. In a highly selected
retrospective chart review of 450 obese or overweight men 18 to
21 years of age from a pediatric endocrinology practice, 11 with
HG (T ¼277 ng/dL) were identied who had been on CC
25 mg/d for at least 3 months by Bendre et al.
125
T increased
signicantly (578 ng/dL), demonstrating in the increasingly
prevalent population that SERMs are a potential therapeutic
modality in obesity-related secondary HG. Body mass index did
not change while on CC but the study only looked at 3-month
results and lifestyle modication was not a part of this review.
The results are encouraging and warrant further evaluation as to
the potential benet of T normalization in the obese young man
with or without lifestyle modication.
The question arises as to whether treatment with CC results in
long-term improvement in T levels. Is the hypothalamic ther-
mostatreset? Marconi et al
126
evaluated 30 men with late-onset
(50 years of age) symptomatic secondary HG (245 ng/dL) on
CC 50 mg. Twenty-seven (90%) normalized their T (>317 ng/dL)
at 3 months (654 ng/dL). Then, CC was discontinued and the
responders were re-evaluated at 3 and 6 months after discontinu-
ation. At 3 and 6 months, 22% and 0% remained eugonadal,
demonstrating the inability to correct the inherent defect with CC
alone. Lifestyle modication was not undertaken. The lack of a
PCBO arm, small numbers, and short duration of the study make
the 38% symptomatic improvement in sexual desire (the pre-
dominant symptomatic complaint) on treatment difcult to
interpret. Perhaps a longer exposure might be of more benet.
ENCLOMIPHENE AND SECONDARY HG
Recent interest has emerged regarding the pharmacology of
CC, which exists as a mixture of two diastereoisomers. EC
composes 62% and has a half-life of 10.5 hours, and ZU com-
poses 38% and has a half-life of 30 days.
127
Although EC
functions as an ER antagonist or agonist depending on the tissue
it is bound to, ZU functions as an ER agonist at high concen-
trations.
128
Due to the longer half-life of ZU, it might be
expected that over time it would become the predominant
isomer in the serum. Helo et al
129
examined the ratio of EC to
ZU in men on long-term CC therapy. Levels of each isomer were
measured in 15 men who were on CC for a median treatment
duration of 25.9 months. Patients showed an increase in total
T of 138.0% and the median ZU-EC ratio was 20:1. Despite
CC being formulated in a nearly 2:1 EC-ZU ratio, ZU was the
predominant isomer present after at least 6 weeks of treatment,
which could have counterproductive effects if ZU functions as an
estrogen agonist at high concentrations. This observation has led
some to investigate the utility of using the pure EC isomer in the
treatment of men with HG.
Wiehle et al
130
published their pharmacokinetic study of 44
men randomized to EC (6.25, 12.5, or 25 mg) daily or daily
transdermal T. All groups showed an increase in total T; the most
robust response was in the EC 25 mg/d group with a total T level
of 586 ng/dL compared with the transdermal T group at 546 ng/
dL. The difference was not statistically signicant. Wiehle et al
131
subsequently published a randomized, double-blinded, PCBO-
controlled study of 73 men with HG (T <250 ng/dL)
investigating the effects of EC (12.5 or 25 mg/d), daily trans-
dermal T, and PCBO. Similar to their previous study, all
treatment groups showed an increase in total T; the most robust
increase was in the EC 12.5 mg group, with 217.2 ng/dL at
baseline to 471.9 ng/dL at 3 months. The EC groups boasted the
added benet of preservation of sperm counts, whereas 54% of
men treated with topical T developed OS compared with 14.6%
in the EC group.
As with CC, Kaminetsky et al
132
found no lasting effect on the
hypothalamic-pituitary-thyroid axis in a 6-month randomized
open-label comparator trial of EC (25 mg) vs T gel in men with
secondary HG (mean T ¼165 ng/dL, mean age ¼46 years).
After 1 month of discontinuation, T levels returned to pre-
treatment levels. All men had previously been on exogenous
therapy and there was no attempt at lifestyle modication.
Sex Med Rev 2017;-:1e22
Cherchez La Femme15
Kim et al
133
reported on the results of two randomized,
double-blinded, double-dummy, PCBO, multicenter, 16-week
phase 3 trials to evaluate T gel 1.62% and two doses of CC
(12.5 and 25 mg) on hormone levels, SC, and testicular volume
in overweight men with secondary HG (T <210 ng/dL).
Oligospermia was exclusionary at a baseline mean SC of well over
75 million/cm
3
. A composite end point of men achieving an SC
higher than 10 million/cm
3
and total T in the normal range was
used. EC was found to meet the end point of 63.5% vs 24.7%
and 5.8% in the T gel and PCBO groups. The T gel and EC
were superior to PCBO in increasing serum T over a 24-hour
sampling period at 16 weeks, but EC demonstrated more
consistent levels (lower coefcients of variation) and signicantly
(P¼.03) more individuals in the normal T range (100e1,040
ng/dL). The investigators speculated that the wide variation of
total T in the topical treatment group resulted from application
issues of the T gel (ie, rushing application, not applying a full
dose by leaving gel in the vial, washing the dose away from hands
before fully absorbed), from skin thickness differences between
patients, or from the timing of application. Fifty men (21%)
developed AEs, although there was no difference of treatment-
related AEs among the three treatment groups.
SERM METABOLISM AND ITS IMPACT ON
EFFICACY
Interest in the metabolism of SERMs emerged from their use
in women, where 8% to 30% of anovulatory women or patients
with ER-positive breast cancer treated with SERMs did not
respond to or developed resistance against SERMs.
134,135
Due to
the lack of long-term controlled trials, resistance and tachyphy-
laxis data in men treated with SERMs are lacking and limited to
case reports of men who had a paradoxical decrease in T or a
negative impact on sperm parameters.
136e138
SERMs are meta-
bolically activated by the CYP450 enzyme encoded primarily by
the CYP2D6 gene.
134,139,140
Genetic polymorphisms in the
CYP2D6 gene affect the catalytic activity of the CYP2D6
enzyme in the metabolism of SERMs.
139e145
Rapid or ineffec-
tive metabolism can result in inadequate levels of active metab-
olites. Human urine metabolite proles suggest a similar
metabolism for (Z)-TF and (E)-clomiphene.
146
CC and TF
exhibit similar actions because of the analogous structural rela-
tion between the 4-hydroxy moiety that binds to the ER in
4-OH-clomiphene and 4-hydroxytamoxifen.
47
Data from
Ghobadi et al
134
showed that the metabolism of CC in healthy
volunteers differs according to genotype of CYPD26 enzyme.
Subjects who were deemed extensive metabolizersshowed
extensive metabolism of (E)-clomiphene, with an area under the
curve 10 times higher for (Z)-clomiphene compared with
(E)-clomiphene. Patients with two non-functional alleles were
unlikely to reach plasma levels of the active metabolites that were
sufcient to block ER activity.
140
Furthermore, research in
women with breast cancer supported dose escalation in patients
whose CYP2D6 enzymes were poor metabolizersof
TF.
134,147e149
Dose escalation according to CYP2D6 activity
has not been studied in men treated with SERMs, although some
clinicians advocate titrating CC based on target T level, which
could be based on this concept of genetic polymorphisms of the
CYP2D6 gene or the ER.
121,136
ADVERSE EVENTS WITH SERMS
Roch et al
150
reported visual changes in four of 58% of
women on CC. Scotomata were documented in one woman
(CC ¼100 mg/d) that resolved after discontinuation and
returned after a CC rechallenge. A second woman (CC ¼200
mg/d) had a decrease in her visual acuity 6 days into therapy that
disappeared after discontinuation but recurred after a repeat
challenge. Two other women (100 mg and 200 mg/d) developed
phosphenes, a phenomenon characterized by the experience of
seeing lights without light actually entering the eye. Ophthal-
mologic examination was normal in one and not performed in
the other. The phosphenes disappeared after discontinuation of
the CC. In a literature review of 35 articles and abstracts of men
and women on CC, Viola et al
151
reported an incidence of visual
AEs with the use of CC of 1.5%. These included blurred vision,
photophobia, diplopia, scotomata, phosphenes, and periph-
lebitis. Three cases of central venous occlusion associated with
CC were identied. The investigators suggested that physicians
should be aware of the potential risk of CC-induced visual dis-
turbances. Ophthalmologic examinations were prospectively
done in all men in the EC registry trial before and after treat-
ment, with no reported ophthalmologic AEs.
Wibowo et al
152
performed a review of reported AEs with the
use of TF in men. Three randomized controlled trials reported
serious AEs. None were considered to have been related to study
treatment. No mortalities were reported in the randomized
controlled trials. In non-randomized controlled trials for infer-
tility (177 men), documented AEs included decreased libido, hot
ashes, hair loss, and weight gain in 7, 2, 2, and 1 men
respectively. All infertility studies were shorter than 6 months.
No ophthalmologic AEs were reported in the review.
In the recently concluded PCBO randomized controlled trial
of EC, Kim et al
133
reported no difference in the incidence of
treatment-related AEs between treatment groups in the safety
population (256 men) over 16 weeks. No AEs occurred more
frequently in the EC-treated men than in the PCBO group. The
one death (stroke) was not judged to be related to study drug and
was attributed to underlying medical conditions. Baseline and
follow-up ophthalmologic examinations were performed and no
ophthalmologic safety issues were reported.
SERMs have been used in millions of women with breast
cancer since the early 2000s. In the long-term trials of the
SERMs for breast cancer, a high-risk population for venous
thromboembolic events (VTEs), there is a slight increase in
VTEs over PCBO. The risk of VTEs in the general population is
0.12% per year. The risk of VTEs in women on hormone
replacement therapy is 0.2% to 0.5% per year. In the
Sex Med Rev 2017;-:1e22
16 Helo et al
Anastrozole, Tamoxifen, and Alone or In Combination (ATAC)
trial, the risk of VTEs on SERMs was 0.34% per year. At 4 years,
women in the SERM arm had a 1.7 relative risk of VTEs.
153
It is
not clear how those risks translate to a younger, lower risk,
infertile or an older, HG, non-cancer male population and
whether the risks increase with the lifetime therapy required for
the long-term therapy of secondary HG.
CONCLUSION
A strong body of evidence supporting the off-label use of
SERMs for the treatment of symptomatic men with secondary
HG exists, particularly in producing T in the eugonadal range,
yet there is no generalized consensus about the use of SERMs in
the treatment of secondary HG. Rigorous long- and short-term
PCBO-controlled studies looking at the symptoms of HG in
men treated with SERMs are lacking. Although all FDA-
approved exogenous replacement strategies have the effect of
decreasing fertility and suppressing the hypothalamic-pituitary
gonadal axis, SERMs use endogenous physiologic mechanisms
to normalize T and preserve and possibly improve fertility.
In addition, unlike replacement strategies, there is no risk of
abuse potential. The benecial effect of SERMs seems limited to
during its use and long-term treatment is likely to be required.
The natural history of secondary HG is unclear. Whether men
with secondary HG will eventually progress to primary HG and
require exogenous treatment remains to be determined. Tachy-
phylaxis and/or acquired resistance to SERMs has not been
demonstrated in men treated for infertility or HG but has been
noted in breast cancer where ER mutations are more likely to
occur. Further studies are needed to establish denitive data on
the optimal dose and effect of SERMs on HG symptoms and
safety in men and its use in growing population of obese men
with HG with and without lifestyle modication. As with the
SERMs in infertility, if prescribed for secondary HG, patients
must be advised of their off-label use and with proper informed
consent and shared decision making.
Corresponding Author: Andrew McCullough, MD, Depart-
ment of Urology, Lahey Hospital and Medical Center Burling-
ton, Burlington, MA, USA; E-mail: mccula01@gmail.com
Conicts of Interest: S.H. and B.W. declare no conicts of
interest. A.M. has purchased stock from Pzer; was on the
Speakers Bureau at Endo; served as a Consultant and Research
Support, and purchased stock at Repros; served as Researcher
Support for Antares; served as a Consultant for Mero Biopharma;
and served as a Consultant for Lipocine.
Funding: None.
STATEMENT OF AUTHORSHIP
Category 1
(a) Conception and Design
Andrew McCullough
(b) Acquisition of Data
Sevann Helo; Blake Wynia; Andrew McCullough
(c) Analysis and Interpretation of Data
Sevann Helo; Blake Wynia; Andrew McCullough
Category 2
(a) Drafting the Article
Sevann Helo; Blake Wynia; Andrew McCullough
(b) Revising It for Intellectual Content
Andrew McCullough
Category 3
(a) Final Approval of the Completed Article
Andrew McCullough
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