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Sex Hormones

Author: Larry H Bernstein, MD, FCAP

A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be
grouped into five groups by the receptors to which they bind:

  • glucocorticoids,
  • mineralocorticoids,
  • androgens,
  • estrogens, and
  • progestogens.
  • Vitamin D derivatives, are a sixth closely related hormone system with homologous receptors. They have some of the characteristics of true steroids as receptor ligands.

Steroid hormones help control metabolism, inflammation, immune functions, salt
and water balance, development of sexual characteristics, and the ability to withstand
illness and injury. The term steroid describes both hormones produced by the body
and artificially produced medications that duplicate the action for the naturally occurring steroids

The natural steroid hormones are generally synthesized from cholesterol in the gonads and adrenal glands. These forms of hormones are lipids. They can pass through the cell membrane as they are fat-soluble,[4] and then bind to steroid hormone receptors (which may be nuclear or cytosolic depending on the steroid hormone) to bring about changes within the cell. Steroid hormones are generally carried in the blood, bound to specific carrier proteins such as sex hormone-binding globulin or corticosteroid-binding globulin. Further conversions and catabolism
occurs in the liver, in other “peripheral” tissues, and in the target tissues.

Synthetic steroids and sterols

A variety of synthetic steroids and sterols have also been contrived. Most are
steroids, but some non-steroidal molecules can interact with the steroid receptors
because of a similarity of shape. Some synthetic steroids are weaker or stronger
than the natural steroids whose receptors they activate.

Some examples of synthetic steroid hormones:
Glucocorticoids: alclometasone, prednisone, dexamethasone, triamcinolone
Mineralocorticoid: fludrocortisone
Vitamin D: dihydrotachysterol
Androgens: apoptone, oxandrolone, oxabolone, testosterone, nandrolone (also
known as anabolic steroids)
Estrogens: diethylstilbestrol (DES)
Progestins: danazol, norethindrone, medroxyprogesterone acetate,
17-Hydroxyprogesterone caproate.

Some steroid antagonists:
Androgen: cyproterone acetate
Progestins: mifepristone, gestrinone
http://www.en.wikipedia.org/wiki/Steroid

Steroid-Hormone-Synthesis

Steroid-Hormone-Synthesis

Steroidogenesis

Steroidogenesis


http://www.gfmer.ch/Books/Reproductive_health/Image171.gif

The regulation of spermatogenesis by androgens

Lee B. Smith, William H. Walker
Seminars in Cell & Developmental Biology 30 (2014) 2–13
http://dx.doi.org/10.1016/j.semcdb.2014.02.012

Testosterone is essential for maintaining spermatogenesis and male fertility.
However, the molecular mechanisms by which testosterone acts have not
begun to be revealed until recently. With the advances obtained from the use
of transgenic mice lacking or overexpressing the androgen receptor, the cell
specific targets of testosterone action as well as the genes and signaling pathways
that are regulated by testosterone are being identified. In this review, the critical
steps of spermatogenesis that are regulated by testosterone are discussed as well
as the intracellular signaling pathways by which testosterone acts. We also review
the functional information that has been obtained from the knock out of the androgen
receptor from specific cell types in the testis and the genes found to be regulated
after altering testosterone levels or androgen receptor expression.

The essence of female–male physiological dimorphism: Differential Ca2+-homeostasis
enabled by the interplay between farnesol-like endogenous sesquiterpenoids and
sex-steroids? The Calcigender paradigm

Arnold De Loof
General and Comparative Endocrinology 211 (2015) 131–146
http://dx.doi.org/10.1016/j.ygcen.2014.12.003

Ca2+ is the most omnipresent pollutant on earth, in higher concentrations a real
threat to all living cells. When [Ca2+]i rises above 100 nM (=resting level), excess
Ca2+ needs to be confined in the SER and mitochondria, or extruded by the different
Ca2+-ATPases. The evolutionary origin of eggs and sperm cells has a crucial, yet
often overlooked link with Ca2+-homeostasis. Because there is no goal whatsoever
in evolution, gametes did neither originate ‘‘with the purpose’’ of generating a progeny
nor of increasing fitness by introducing meiosis. The explanation may simply be that
females ‘‘invented the trick’’ to extrude eggs from their body as an escape strategy
for getting rid of toxic excess Ca2+ resulting from a sex-hormone driven increased
influx into particular cells and tissues.
The production of Ca2+-rich milk, seminal fluid in males and all secreted proteins
by eukaryotic cells may be similarly explained. This view necessitates an upgrade
of the role of the RER-Golgi system in extruding Ca2+. In the context of insect
metamorphosis, it has recently been (re)discovered that (some isoforms of) Ca2+-
ATPases act as membrane receptors for some types of lipophilic ligands, in
particular for endogenous farnesol-like sesquiterpenoids (FLS) and, perhaps, for
some steroid hormones as well.
A novel paradigm, tentatively named ‘‘Calcigender’’ emerges. Its essence is: gender-
specific physiotypes ensue from differential Ca2+-homeostasis enabled by genetic
differences, farnesol/FLS and sex hormones. Apparently the body of reproducing
females gets temporarily more poisoned by Ca2+ than the male one, a selective
benefit rather than a disadvantage.

Sex differences in the expression of estrogen receptor alpha within noradrenergic
neurons in the sheep brain stem

J.L. Rose, A.S. Hamlin, C.J. Scott
Domestic Animal Endocrinology 49 (2014) 6–13
http://dx.doi.org/10.1016/j.domaniend.2014.04.003

In female sheep, high levels of estrogen exert a positive feedback action
on gonadotropin releasing hormone (GnRH) secretion to stimulate a surge in
luteinizing hormone (LH) secretion. Part of this action appears to be via brain
stem noradrenergic neurons. By contrast, estrogen action in male sheep has
a negative feedback action to inhibit GnRH and LH secretion. To investigate
whether part of this sex difference is due to differences in estrogen action in
the brain stem, we tested the hypothesis that the distribution of estrogen
receptor a (ERα) within noradrenergic neurons in the brain stem differs
between rams and ewes. To determine the distribution of ERα, we used
double-label fluorescence immunohistochemistry for dopamine b-Hydroxylase,
as a marker for noradrenergic and adrenergic cells, and ERα. In the ventro-
lateral medulla (A1 region), most ERα-immunoreactive (-ir) cells were
located in the caudal part of the nucleus. Overall, there were more ERα-ir
cells in rams than ewes, but the proportion of double-labeled cells was did
not differ between sexes. Much greater numbers of ERα–ir cells were
found in the nucleus of the solitary tract (A2 region), but <10% were double
labeled and there were no sex differences. The majority of ERα-labeled cells
in this nucleus was located in the more rostral areas. Erα labeled cells were
found in several rostral brain stem regions but none of these were double
labeled and so were not quantified. Because there was no sex difference
in the number of ERα-ir cells in the brain stem that were noradrenergic,
the sex difference in the action of estrogen on gonadotropin secretion in
sheep is unlikely to involve actions on brain stem noradrenergic cells.

Androgens, estrogens, and second messengers

William Rosner, DJ Hryb, MS Khan, AM Nakhla, and NA Romas
Steroids 1998; 63:278 –281 PII S0039-128X(98)00017-8

Over the course of the last four decades, a detailed understanding of the
molecular mechanisms by which steroid hormones exert their effects has
evolved, and continues to evolve. The major focus of research in this area
has been on the manner in which steroid receptors activate transcription.
Pathways of steroid action other than by direct interaction with intracellular
receptors have received relatively little attention. However, there is a growing
body of evidence that steroid hormones exert effects through mechanisms
in addition to those involving their classic intracellular receptors. One such
mechanism is based on the observation that a number of cells have receptors
on their plasma membranes for the plasma protein, sex hormone binding
globulin (SHBG). It is the purpose of this review to briefly describe our current
knowledge of this system.

SHBG binds to a receptor (RSHBG) on cell membranes cAMP and the steroid-SHBG-RSHBG system
Biology of the SHBG-RSHBG system

Relation between the affinity of steroid for SHBG and its potency in inhibiting
the binding of SHBG to RSHBG.

KA (SHBG) = Association constant for SHBG and the indicated steroid.
Ki SHBG-RSHBG = The inhibition constant for the indicated steroid on the
binding of SHBG to RSHBG.

PSA secretion was stimulated by DHT. Although estradiol alone had no effect
on PSA secretion, it caused an increase equal to that seen with DHT if the
prostate tissue was first loaded with SHBG, e.g., if RSHBG was occupied by
SHBG. Because estradiol-SHBG increases intracellular cAMP, we ascertained
whether other compounds that raise cAMP (forskolin), or cAMP itself, could
increase PSA secretion. Such was the case. cAMP begins its signal cascade
by activating protein kinase A (PKA) so that if estradiol-SHBG increases PSA
secretion by a mechanism involving cAMP, inhibition of PKA should block
estradiol-SHBG-initiated PSA secretion. Estradiol-SHBG failed to stimulate
PSA when PKA was inhibited with PKI. On the other hand, DHT-stimulated
PSA secretion, which does not involve PKA, was not inhibited by PKI. That
the effect of estradiol-SHBG was independent of the estrogen receptor was
shown by the lack of inhibition of estrogen-stimulated PSA secretion by two
anti-estrogens, tamoxifen and ICI 164,284. The promoter of the PSA gene
has an androgen response element, and both PSA secretion and the
expression of PSA mRNA are androgen-regulated. We investigated the
effect of hydroxyflutamide and cyproterone acetate. Both potent anti-
androgens, on the E2-SHBG-mediated increase in PSA secretion. secretion.
They also blocked the effect of E2-SHBG on PSA secretion. Since E2 is
not exerting its effect by binding to the AR, e.g., it is not its cognate ligand,
the E2-induced secretion of PSA observed in this study reflects ligand-
independent activation of the AR.26 Thus, estradiol activates a typical
AR-mediated event, PSA synthesis and secretion, by activating SHBG-
RSHBG. These data make clear the fact that there is cross-talk between a
steroid hormone-engendered event at the cell membrane and a classic
intracellular steroid hormone receptor.
Abbreviations: PSA, prostate specific antigen; DHT, dihydrotestosterone;
E2, estradiol; PKI, inhibitor of protein kinase A; ICI 164,384 (a pure anti-
estrogen); 2MeOE2, 2 methoxyestradiol; Cypro, cyproterone acetate,
OHFlut, hydroxyflutamide.

Role of G protein-coupled estrogen receptor 1, GPER, in inhibition of oocyte
maturation by endogenous estrogens in zebrafish

Yefei Pang, Peter Thomas
Developmental Biology 342 (2010) 194–206
http://dx.doi.org:/10.1016/j.ydbio.2010.03.027

Estrogen inhibition of oocyte maturation (OM) and the role of GPER (formerly
known as GPR30) were investigated in zebrafish. Estradiol-17β (E2) and G-1,
a GPER-selective agonist, bound to zebrafish oocyte membranes suggesting
the presence of GPER which was confirmed by immunocytochemistry using
a specific GPER antibody. Incubation of follicle-enclosed oocytes with an
aromatase inhibitor, ATD, and enzymatic and manual removal of the ovarian
follicle cell layers significantly increased spontaneous OM which was partially
reversed by co-treatment with either 100 nM E2 or G-1. Incubation of
denuded oocytes with the GPER antibody blocked the inhibitory effects of
estrogens on OM, whereas microinjection of estrogen receptor alpha (ERα)
antisense oligonucleotides into the oocytes was ineffective. The results
suggest that endogenous estrogens produced by the follicle cells inhibit or
delay spontaneous maturation of zebrafish oocytes and that this estrogen
action is mediated through GPER. Treatment with E2 and G-1 also attenuated
the stimulatory effect of the teleost maturation-inducing steroid, 17,20 β-
dihyroxy-4-pregnen-3-one (DHP), on OM.  Moreover, E2 and G-1 down-
regulated the expression of membrane progestin receptor alpha (mPRα),
the intermediary in DHP induction of OM. Conversely DHP treatment caused
a N50% decline in GPER mRNA levels. The results suggest that estrogens
and GPER are critical components of the endocrine system controlling
the onset of OM in zebrafish. A model is proposed for the dual control of the
onset of oocyte maturation in teleosts by estrogens and progestins acting
through GPER and mPRα, respectively, at different stages of oocyte
development.
Reprint of ’’GPR30 mediates estrogen rapid signaling and neuroprotection’’

Hui Tang, Q Zhang, L Yang, Y Dong, M Khan, F Yang, DW Brann, R Wang
Molecular and Cellular Endocrinology 389 (2014) 92–98
http://dx.doi.org/10.1016/j.mce.2014.01.024
http://dx.doi.org/10.1016/j.mce.2014.05.005

G-protein-coupled estrogen receptor-30 (GPR30), also known as G-protein
estrogen receptor-1 (GPER1), is a putative extranuclear estrogen receptor
whose precise functions in the brain are poorly understood. Studies using
exogenous administration of the GPR30 agonist, G1 suggests that GPR30
may have a neuroprotective role in cerebral ischemia. However, the
physiological role of GPR30 in mediating estrogen (E2)-induced neuro-
protection in cerebral ischemia remains unclear. Also unclear is whether
GPR30 has a role in mediating rapid signaling by E2 after cerebral ischemia,
which is thought to underlie its neuroprotective actions. To address these
deficits in our knowledge, the current study examined the effect of antisense
oligonucleotide (AS) knockdown of GPR30 in the hippocampal CA1 region
upon E2-BSA induced neuroprotection and rapid kinase signaling in a rat
model of global cerebral ischemia (GCI). Immunohistochemistry demonstrated
that GPR30 is strongly expressed in the hippocampal CA1 region and
dentate gyrus, with less expression in the CA3 region. E2-BSA exerted
robust neuroprotection of hippocampal CA1 neurons against GCI, an effect
abrogated by AS knockdown of GPR30. Missense control oligonucleotides had
no effect upon E2-BSA-induced neuroprotection, indicating specificity of the
effect. The GPR30 agonist, G1 also exerted significant neuroprotection against
GCI. E2-BSA and G1 also rapidly enhanced activation of the prosurvival
kinases, Akt and ERK, while decreasing proapototic JNK activation. Importantly,
AS knockdown of GPR30 markedly attenuated these rapid kinase signaling
effects of E2-BSA. As a whole, the studies provide evidence of an important
role of GPR30 in mediating the rapid signaling and neuroprotective actions
of E2 in the hippocampus.
Regulation of brain microglia by female gonadal steroids

Pardes Habib, Cordian Beyer
Journal of Steroid Biochemistry & Molecular Biology 2015; 146: 3–14
http://dx.doi.org/10.1016/j.jsbmb.2014.02.018

Microglial cells are the primary mediators of the CNS immune defense system
and crucial for shaping inflammatory responses. They represent a highly
dynamic cell population which is constantly moving and surveying their
environment. Acute brain damage causes a local attraction and activation of
this  immune cell type which involves neuron-to-glia and glia-to-glia interactions.
The prevailing view attributes microglia a “negative” role such as defense and
debris elimination. More topical studies also suggest a protective and “positive”
regulatory function. Estrogens and progestins exert anti-inflammatory and
neuroprotective effects in the CNS in acute and chronic brain diseases.
Recent work revealed that microglial cells express subsets of classical and
non-classical estrogen and progesterone receptors in a highly dynamic way.
In this review article, we would like to stress the importance of microglia for
the spreading of neural damage during hypoxia, their susceptibility to functional
modulation by sex steroids, the potency of sex hormones to switch microglia
from a pro-inflammatory M1 to neuroprotective M2 phenotype, and the
regulation of pro-and anti-inflammatory properties including the inflammasome.
We will further discuss the possibility that the neuroprotective action of sex
steroids in the brain involves an early and direct modulation of local microglia
cell function. Neuroprotection by gonadal steroid hormones in acute brain
damage requires cooperation with astroglia and microglia

Sonja Johann, Cordian Beyer
http://dx.doi.org/10.1016/j.jsbmb.2012.11.006

The neuroactive steroids 17β-estradiol and progesterone control a broad
spectrum of neural functions. Besides their roles in the regulation of classical
neuroendocrine loops, they strongly influence motor and cognitive systems,
behavior, and modulate brain performance at almost every level. Such a
statement is underpinned by the widespread and lifelong expression pattern
of all types of classical and non-classical estrogen and progesterone receptors
in the CNS. The life-sustaining power of neurosteroids for tattered or seriously
damaged neurons aroused interest in the scientific community in the past years
to study their ability for therapeutic use under neuropathological challenges.
Documented by excellent studies either performed in vitro or in adequate animal
models mimicking acute toxic or chronic neuro-degenerative brain disorders,
both hormones revealed a high potency to protect neurons from damage
and saved neural systems from collapse. Unfortunately, neurons, astroglia,
microglia, and oligodendrocytes are comparably target cells for both steroid
hormones. This hampers the precise assignment and understanding of
neuroprotective cellular mechanisms activated by both steroids. In this article,
we strive for a better comprehension of the mutual reaction between these
steroid hormones and the two major glial cell types involved in the maintenance
of brain homeostasis, astroglia and microglia, during acute traumatic brain
injuries such as stroke and hypoxia. In particular, we attempt to summarize
steroid-activated cellular signaling pathways and molecular responses in these
cells and their contribution to dampening neuroinflammation and neural
destruction.

Photoperiod influences the ontogenetic expression of aromatase
and estrogen receptor α in the developing tilapia brain.

Li-Hsueh Wang, Ching-Lin Tsai
General and Comparative Endocrinology 2006; 145: 62–66
http://dx.doi.org:/10.1016/j.ygcen.2005.07.004

Neural development is determined not only by genetic regulation, but also
by environmental cues. Central estrogen-forming/estrogen-sensitive systems
play an important role in the neural development of the brain. In the present
study, the quantitative reverse transcription-polymerase chain reaction method
was used to investigate the effects of photoperiod on the ontogenetic
expression of aromatase and estrogen receptor a (ERα) in the developing
tilapia brain. Before day 5 post-hatch, brain aromatase mRNA expression was
significantly decreased by constant light but not influenced by constant darkness.
During this period, brain ERα mRNA expression was significantly increased
under both constant light and constant darkness. Between days 5 and 10, and
between days 10 and 15, neither brain aromatase nor brain ERα expression
was altered under constant darkness and constant light. These results indicate
that the ontogenetic expression of brain aromatase and brain ERα is not via a
light-inducing process but influenced by a light-entraining signal during the
very early period of development.

Orphanin FQ-ORL-1 Regulation of Reproduction and Reproductive Behavior in
the Female

Kevin Sinchak, Lauren Dalhousay, Nayna Sanathara
Vitamins and Hormones 187-220.  http://dx.doi.org/10.1016/bs.vh.2014.11.002

Orphanin FQ (OFQ/N) and its receptor, opioid receptor-like receptor-1 (ORL-1),
are expressed throughout steroid-responsive limbic and hypothalamic circuits
that regulate female ovarian hormone feedback and reproductive behavior
circuits. The arcuate nucleus of the hypothalamus (ARH) is a brain region
that expresses OFQ/N and ORL-1 important for both sexual behavior and
modulating estradiol feedback loops. Within the ARH, the activation of the
OFQ/N-ORL-1 system facilitates sexual receptivity (lordosis) through the
inhibition of β-endorphin neuronal activity. Estradiol initially activates ARH
β-endorphin neurons to inhibit lordosis. Simultaneously, estradiol upregulates
coexpression of OFQ/N and progesterone receptors and ORL-1 in ARH
β-endorphin neurons. Ovarian hormones regulate pre- and postsynaptic
coupling of ORL-1 to its G protein-coupled signaling pathways. When the
steroid-primed rat is nonreceptive, estradiol acts pre- and postsynaptically
to decrease the ability of the OFQ/N-ORL-1 system to inhibit ARH β-endorphin
neurotransmission. Conversely, when sexually receptive, ORL-1 signaling is
restored to inhibit β-endorphin neurotransmission. Although steroid signaling
that facilitates lordosis converges to deactivate ARH.
Estradiol Activates the Prostate Androgen Receptor and Prostate specific Antigen
Secretion through the Intermediacy of Sex Hormone-binding Globulin

Atif M. Nakhla, Nicholas A. Romas, and William Rosner
J Biol Chem Mar 14, 1997; 272(11): 6838–6841 http://www-jbc.stanford.edu/jbc/

These experiments were designed to examine the relationship between the
effects of steroid hormones mediated by classic intracellular steroid hormone
receptors and those mediated by a signaling system subserved at the plasma
membrane by a receptor for sex hormone binding globulin. It is known that
unliganded sex hormone-binding globulin (SHBG) binds to a receptor (RSHBG)
on prostate membranes. The RSHBG*SHBG complex is rapidly activated by
estradiol to stimulate adenylate cyclase, with a resultant increase in intracellular
cAMP. In this paper we examine the effect of this system on a prostate gene
product known to be activated by androgens, prostate-specific antigen.
We have shown previously that estradiol (E2) participates in a signaling
system that originates, not within the cell, but at the plasma membrane.
Through the intermediacy of the plasma protein, sex hormone-binding
globulin (SHBG), it causes the generation of cAMP. In brief, unliganded
SHBG binds to a receptor (RSHBG) on certain cell surfaces and the
RSHBG*SHBG complex is rapidly activated by E2 to stimulate adenylate cyclase,
with a resultant increase in intracellular cAMP. There is a paucity of information
on events subsequent to the generation of cAMP by this system. In this paper
we examine the effect of E2-SHBG-RSHBG on an androgen responsive gene.
The gene for prostate-specific antigen (PSA) contains an androgen response
element. After binding its cognate ligand, the androgen receptor (AR) interacts
with this response element to initiate PSA mRNA transcription and secretion.
We show that, in the absence of androgens, E2 in concert with SHBG*RSHBG,
acts at the cell membrane to cause secretion of PSA and that this effect is
blocked by anti-androgens. This observation provides a first functional link
between a classic steroid hormone receptor and a cell membrane-mediated
steroidal effect. In serum-free organ culture of human prostates,
dihydrotestosterone caused an increase in prostate specific antigen secretion.
This event was blocked by the anti-androgens cyproterone acetate and
hydroxyflutamide. In the absence of androgens, estradiol added to prostate
tissue, whose RSHBG was occupied by SHBG, reproduced the results seen
with dihydrotestosterone. Neither estradiol alone nor SHBG alone duplicated
these effects. The estradiol*SHBG-induced increase in prostate-specific
antigen was not blocked by anti-estrogens, but was blocked both by anti-
androgens and a steroid (2-methoxyestradiol) that prevents the binding of
estradiol to SHBG. Furthermore, an inhibitor of protein kinase A prevented
the estradiol*SHBG-induced increase in prostate-specific antigen but not
that which followed dihydrotestosterone. These data indicate that there is a
signaling system that amalgamates steroid-initiated intracellular events
with steroid-dependent occurrences generated at the cell membrane and
that the latter signaling system proceeds by a pathway that involves protein
kinase A.
Mechanisms of crosstalk between endocrine systems: Regulation of sex steroid
hormone synthesis and action by thyroid hormones

Paula Duarte-Guterman, Laia Navarro-Martín, Vance L. Trudeau
General and Comparative Endocrinology 203 (2014) 69–85
http://dx.doi.org/10.1016/j.ygcen.2014.03.015

Thyroid hormones (THs) are well-known regulators of development and
metabolism in vertebrates. There is increasing evidence that THs are also
involved in gonadal differentiation and reproductive function. Changes in TH
status affect sex ratios in developing fish and frogs and reproduction
(e.g., fertility), hormone levels, and gonad morphology in adults of species of
different vertebrates. In this review, we have summarized and compared the
evidence for cross-talk between the steroid hormone and thyroid axes and
present a comparative model. We gave special attention to TH regulation of
sex steroid synthesis and action in both the brain and gonad, since these are
important for gonad development and brain sexual differentiation and have
been studied in many species. We also reviewed research showing that
there is a TH system, including receptors and enzymes, in the brains and
gonads in developing and adult vertebrates. Our analysis shows that THs
influences sex steroid hormone synthesis in vertebrates, ranging from fish
to pigs. This concept of crosstalk and conserved hormone interaction has
implications for our understanding of the role of THs in reproduction, and
how these processes may be dysregulated by environmental endocrine
disruptors.
Inverse relationship between hSHBG affinity for testosterone and hSHBG
concentration revealed by surface plasmon resonance

Laurence Heinrich-Balard, Wael Zeinyeh, Henri Déchaud, Pascaline Rivory, et al.
Molecular and Cellular Endocrinology 399 (2015) 201–207
http://dx.doi.org/10.1016/j.mce.2014.10.002

A wide range of human sex hormone-binding globulin (hSHBG) affinity constants
for testosterone (KA_hSHBG) has been reported in literature. To bring new insight
on the KA_hSHBG value, we implemented a study of the molecular interactions
occurring between testosterone and its plasma transport proteins by using
surface plasmon resonance. The immobilization on the sensor-chip of a
testosterone derivative was performed by an oligoethylene glycol linker.
For different plasmas with hSHBG concentrations, an assessment of the
KA_hSHBG was obtained from a set of sensor-grams and curve-fitting these
data.We observed that KA_hSHBG decreased, from at least two decades,
when the plasma hSHBG concentration increased from 4.4 to 680 nmol/L.
Our study shows a wide biological variability of KA_hSHBG that is related
to the hSHBG concentration.
These unexpected results may have a physiological significance and question
the validity of current methods that are recommended for calculating free
testosterone concentrations to evaluate androgen disorders in humans.
Intracrinology in action: Importance of extragonadal sex steroid biosynthesis
and inactivation in peripheral tissues in both women and men.

Editorial
Journal of Steroid Biochemistry & Molecular Biology 145 (2015) 131–132
http://dx.doi.org/10.1016/j.jsbmb.2014.09.012

It seems appropriate, as introduction, to summarize the mechanisms at the
basis of the new paradigm of steroid biosynthesis in the human peripheral
tissues, namely intracrinology. While the first clinical proof of the role of
extragonadal sex steroid biosynthesis was obtained with combined androgen
blockade in men treated for prostate cancer, the first demonstration of the
efficacy of DHEA replacement therapy was on the symptoms of vulvovaginal
atrophy in postmenopausal women; (Archer, this issue).
DHEA is transformed specifically in each cell of each peripheral tissue into
the proper amounts of estrogens and/or androgens, depending upon the
local expression of the appropriate steroid forming enzymes; (Labrie, this issue).
Most importantly, the sex steroids synthesized and acting intracellularly in
peripheral tissues are also inactivated locally before being released in the
extracellular space, thus maintaining the serum levels of estradiol and
testosterone at biologically inactive concentrations, thus avoiding systemic
exposure to sex steroids during menopause as well illustrated by atrophy
of the endometrium.
As mentioned above, that extragonadal androgen biosynthesis is clinically
important became obvious in 1982 when the addition of the antiandrogen
flutamide to castration provided very exciting and unexpected beneficial results
(Labrie, this issue). In fact, combining a pure anti-androgen to castration has
been the first treatment shown to prolong life in prostate cancer and very clearly
confirmed by the prolongation of life of 2.2–4.8 months observed following
addition of MDV-3100 or abiraterone to castration resistant prostate cancer
patients (Grist et al., this issue). (Mizokami et al., this issue) very competently
complement the mechanisms potentially involved in extragonadal steroid
biosynthesis. A repeated observation is the association between serum DHEA
levels and increased longevity, a subject reviewed by Ohlsson et al., this issue.
Most importantly, a subject which remains to be supported by long-term clinical
trials but which shows very promising preclinical data is the possibility of a
beneficial effect of DHEA on brain functions, especially cognition, memory
and delayed development of mild cognitive impairment and Alzheimer’s
disease (see Starka et al.; Soma et al; Pluchino et al; Maggio et al.; Hill et al.,
this issue). The information summarized in the very up-to-date manuscripts
of this special JSBMB issue has the potential of opening the way to a prodrug
replacement therapy already well illustrated on the symptoms and signs of
vulvovaginal atrophy and sexual dysfunction (Archer, this issue). The
administration to sex steroid deficient women of an appropriate amount of
DHEA able to correct the symptoms of vulvovaginal atrophy (mostly estrogen-
sensitive) and sexual dysfunction (androgen-sensitive), and potentially, in the
future, other problems of menopause, does permit to the sex steroid-deficient
women to benefit from a normal/sufficient level of sex steroids in specific tissues
using the enzymes developed over 500 million years to permit a better quality
of life during the menopausal years.

Inactivation of androgens by UDP-glucuronosyltransferase enzymes in humans

Alain Belanger, Georges Pelletier, Fernand Labrie, Olivier Barbier and Sarah Chouinard
TRENDS in Endocrinology and Metabolism 2003; 14(10):473-78
http://dx.doi.org:/10.1016/j.tem.2003.10.005

In humans, 3b-hydroxysteroid dehydrogenase (3β-HSD), 17β-HSD and
5α-reductase activities in androgen target tissues, such as the prostate and
skin, convert dehydroepiandrosterone, androstenedione and testosterone into
the most potent natural androgen dihydrotestosterone (DHT). This androgen
is converted mainly in situ into two phase I metabolites, androsterone (ADT)
and androstane-3α,17β-diol (3α-DIOL), which might be back converted to DHT.
Here, we discuss the recent findings regarding the characterization of specific
UDP glucuronosyltransferases (UGTs), UGT2B7, B15 and B17, responsible for
the glucuronidation of these metabolites. The tissue distribution and cellular
localization of the UGT2B transcripts and proteins in humans clearly indicate
that these enzymes are synthesized in androgen-sensitive tissues. It is
postulated that the conjugating activity of UGT enzymes is the main mechanism
for modulating the action of steroids and protecting the androgen-sensitive
tissues from deleteriously high concentrations of DHT, ADT and 3α-DIOL.
Synthesis and Evaluation of Potential Radioligands for the Progesterone Receptor

R.M. Hoyte, W. Rosner, I.S. Johnson, J. Zielinski, and R. B. Hochberg
J. Med. Chem. 1985; 28: 1695-1699

Several steroidal analogues were synthesized as potential y-emitting radioligands
for the progesterone receptor. Each of these compounds was tested as an inhibitor
of the specific binding of [3H]-17α,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione
(R5020) to the progesterone receptor in rabbit uterine cytosol. R5020 is a well-
known progestin with high affinity for the receptor. Of the compounds synthesized,
aromatic N-substituted (2-17 steroidal carboxamides inhibited the binding only
poorly. Three compounds, 16α-iodo-4-estren-17β-ol-3-one, 17α-[2(E)-iodovinyl]
-4-estren-17β-ol-3-one, and 17α-[2(Z)-iodovinyl]-4-estren-l7β-ol-3-one are
excellent competitors, each having a Ki less than or equal to that of the natural
progestin, progesterone. Since similar iodinated analogues of estrogens
have been shown to be extremely stable both in vivo and in vitro, these compounds
are potentially useful ligands for the progesterone receptor.

Estradiol concentration and the expression of estrogen receptors in the testes of
the domestic goose (Anser anser f. domestica) during the annual reproductive cycle

Leska, J. Kiezun, B. Kaminska, L. Dusza
Domestic Animal Endocrinology 51 (2015) 96–104
http://dx.doi.org/10.1016/j.domaniend.2014.12.002

Seasonal fluctuations in the activity of bird testes are regulated by a complex mechanism
where androgens play a key role. Until recently, the role played by estrogens in males has
been significantly underestimated. However, there is growing evidence that the proper
functioning of the testes is associated with optimal estradiol (E2) concentration
in both the plasma and testes of many mammalian species. Estrogens are
gradually emerging as very important players in hormonal regulation of
reproductive processes in male mammals. Despite the previously mentioned,
it should be noted that estrogenic action is limited by the availability of
specific receptors – estrogen receptor alpha (ERα) and estrogen receptor beta
(ERβ). Interestingly, there is a general scarcity of information concerning the
estrogen responsive system in the testes of male birds, which is of particular
interest in exploring the phenomenon of seasonality of reproduction. To address
this question, we have investigated for the first time the simultaneous
expression of testicular ERα and ERβ genes and proteins with the
accompanying plasma and testicular E2 concentrations during the annual
reproductive cycle of male bird. The research model was the domestic
goose (Anser anser f. domestica), a species whose annual reproductive
cycle can be divided into 3 distinct phases characterized by changes
in testicular activity. It has been revealed that the stable plasma E2 profile
did not correspond to changing intratesticular E2 profile throughout the
experiment. The expression of ERα and ERβ genes and proteins was detected
in gander testes and it fluctuated on a seasonal basis with lower level in
breeding and sexual reactivation stages and higher level during the
nonbreeding stage. Our results demonstrated changes in testicular sensitivity
to estrogens in male domestic goose during the annual reproductive cycle.
The seasonal pattern of estrogen receptors (ERs) expression was analyzed
against the hormonal background and a potential mechanism of ERs regulation
in bird testes was proposed. The present study revealed seasonal variations
in the estrogen responsive system, but further research is needed to fully
explore the role of estrogens in the reproductive tract of male birds.

Effects of 5α-dihydrotestosterone on expression of genes related to steroidogenesis
and spermatogenesis during the sex determination and differentiation periods of
the pejerrey, Odontesthes bonariensis

Anelisa González, Juan I. Fernandino, Gustavo M. Somoza
Comparative Biochemistry and Physiology, Part A 182 (2015) 1–7
http://dx.doi.org/10.1016/j.cbpa.2014.12.003

Sex steroid hormones are important players in the control of sex differentiation
by regulating gonadal development in teleosts. Although estrogens are clearly
associated with the ovarian differentiation in teleosts, the effects of androgens
on early gonadal development are still a matter of debate. Traditionally,
11-ketotestosterone (11-KT) is considered themajor androgen in fish; however,
5α-dihydrotestosterone (5α-DHT), the most potent androgen in tetrapods, was
recently found in fish testis and plasma, but its physiological role is still unknown.
In this context, the expression of genes associated with steroidogenesis and
spermatogenesis, body growth and sex differentiation were assessed in
Odontesthes bonariensis larvae fed with food supplemented with two doses of
5α-DHT (0.1 and 10 μg/g of food) from hatching to 6 weeks of age. At the lowest
dose, 5α-DHT treated larvae showed an estrogenic gene expression pattern, with
low hsd11β2 and high cyp19α1α and er2 expression levels with no differences
in sex ratio. At the highest dose, 5α-DHT produced a male-shifted sex ratio and
the larvae exhibited a gene expression profile characteristic of an advancement
of spermatogenesis, with inhibition of amh and stimulation of ndrg3. No
differences were observed in somatic growth. These results suggest that in
this species, 5α-DHT could have a role on sex differentiation and its effects
can differ according to the dose.
Do androgens link morphology and behavior to produce phenotype-specific
behavioral strategies?

Douglas G. Barron, Michael S. Webster, Hubert Schwabl
Animal Behaviour 100 (2015) 116e124
http://dx.doi.org/10.1016/j.anbehav.2014.11.016

Morphological and behavioral traits often covary with each other, and the links
between them may arise from shared physiological mechanisms. In particular,
androgens such as testosterone have emerged as prime candidates for linking
behaviour and morphology due to the environmental sensitivity and pleiotropic
effects of these hormones. In this study we investigated the hypothesis that
androgens simultaneously relate to morphological and behavioral variation,
thereby producing the integrated reproductive phenotypes of male red-backed
fairy-wrens, Malurus melanocephalus. Males of this species can adopt one of
three discrete breeding phenotypes: breeding in red/black plumage, breeding
in brown plumage, or remaining as nonbreeding brown natal auxiliaries. Although
the expression of morphological traits in this species is regulated by androgens
and phenotypes differ in baseline androgen levels (red/black breeder > brown
breeder > auxiliary), injection with GnRH failed to expose phenotype specific
constraints on androgen production. Observations of territoriality, nestling
feeding and extraterritorial forays revealed phenotype-specific patterns of mating
and parental effort, yet these were largely related to age and were not correlated
with baseline or GnRH-induced androgen levels, or the androgen change between
these points. While these findings support the idea that morphological and
behavioral traits are linked via phenotypic correlations, they do not support
the hypothesis that behavioral differences arise from variation in circulating
androgens or the capacity to produce them.
Effects of sex steroids on expression of genes regulating growth-related
mechanisms in rainbow trout (Oncorhynchus mykiss)

Beth M. Cleveland, Gregory M. Weber
General and Comparative Endocrinology xxx (2015) xxx–xxx
http://dx.doi.org/10.1016/j.ygcen.2014.11.018

Effects of a single injection of 17b-estradiol (E2), testosterone (T), or
5b-dihydrotestosterone (DHT) on expression of genes central to the
growth hormone (GH)/insulin-like growth factor (IGF) axis, muscle
regulatory factors, transforming growth factor-beta (TGFβ) superfamily
signaling cascade, and estrogen receptors were determined in rainbow
trout (Oncorhynchus mykiss) liver and white muscle tissue. In liver in
addition to regulating GH sensitivity and IGF production, sex
steroids also affected expression of IGF binding proteins, as E2, T,
and DHT increased expression of igfbp2β and E2 also increased
expression of igfbp2 and igfbp4. Regulation of this system also occurred
in white muscle in which E2 increased expression of igf1, igf2, and
igfbp5β1, suggesting anabolic capacity may be maintained in white
muscle in the presence of E2. In contrast, DHT decreased expression
of igfbp5β1. DHT and T decreased expression of myogenin, while other
muscle regulatory factors were either not affected or responded similarly
for all steroid treatments. Genes within the TGFβ superfamily signaling
cascade responded to steroid treatment in both liver and muscle,
suggesting a regulatory role for sex steroids in the ability to transmit
signals initiated by TGFβ superfamily ligands, with a greater number
of genes responding in liver than in muscle. Estrogen receptors were
also regulated by sex steroids, with era1 expression increasing for all
treatments in muscle, but only E2- and T-treatment in liver. E2 reduced
expression of erb2 in liver. Collectively, these data identify how
physiological mechanisms are regulated by sex steroids in a manner
that promotes the disparate effects of androgens and estrogens on
growth in salmonids.
Distribution and function of 3′,5′-Cyclic-AMP phosphodiesterases in the human ovary

T.S. Petersen, S.G. Kristensen, J.V. Jeppesen, .., K.T. Macklon, C.Y. Andersen
Molecular and Cellular Endocrinology 403 (2015) 10–20
http://dx.doi.org/10.1016/j.mce.2015.01.004

The concentration of the important second messenger cAMP is regulated by
phosphodiesterases (PDEs) and hence an attractive drug target. However,
limited human data are available about the PDEs in the ovary. The aim of the
present study was to describe and characterise the PDEs in the human ovary.
Results were obtained by analysis of mRNA microarray data from follicles and
granulosa cells (GCs), combined RT-PCR and enzymatic activity analysis in GCs,
immunohisto-chemical analysis of ovarian sections and by studying the effect
of PDE inhibitors on progesterone production from cultured GCs. We found that
PDE3, PDE4, PDE7 and PDE8 are the major families present while PDE11A
was not detected. PDE8B was differentially expressed during folliculogenesis.
In cultured GCs, inhibition of PDE7 and PDE8 increased basal progesterone
secretion while PDE4 inhibition increased forskolin-stimulated progesterone
secretion. In conclusion, we identified PDE3, PDE4, PDE7 and PDE8 as
the major PDEs in the human ovary.
Diethylstilbestrol can effectively accelerate estradiol-17-O-glucuronidation, while
potently inhibiting estradiol-3-O-glucuronidation

Liangliang Zhu, Ling Xiao, Yangliu Xia, .., Yan Wu, Ganlin Wu, Ling Yang
Toxicology and Applied Pharmacology 283 (2015) 109–116
http://dx.doi.org/10.1016/j.taap.2015.01.003

This in vitro study investigates the effects of diethylstilbestrol (DES), a widely
used toxic synthetic estrogen, on estradiol-3- and 17-O- (E2-3/17-O)
glucuronidation, via culturing human liver microsomes (HLMs) or
recombinant UDP-glucuronosyl-transferases (UGTs) with DES and E2.
DES can potently inhibit E2-3-O-glucuronid-ation in HLM, a probe reaction
for UGT1A1. Kinetic assays indicate that the inhibition follows a competitive
inhibition mechanism, with the Ki value of 2.1 ± 0.3 μM, which is less than
the possible in vivo level. In contrast to the inhibition on E2-3-O-glucuronidation,
the acceleration is observed on E2-17-O-glucuronidation in HLM, in which
cholestatic E2-17-O-glucuronide is generated. In the presence of DES
(0–6.25 μM), Km values for E2-17-Oglucuronidation are located in the
range of 7.2–7.4 μM, while Vmax values range from 0.38 to 1.54 nmol/min/mg.
The mechanism behind the activation in HLM is further demonstrated by
the fact that DES can efficiently elevate the activity of UGT1A4 in catalyzing
E2-17-O-glucuronidation. The presence of DES (2 μM) can elevate Vmax from
0.016 to 0.81 nmol/min/mg, while lifting Km in a much lesser extent from 4.4 to
11 μM. Activation of E2-17-O-glucuronidation is well described by a two binding
site model, with KA, α, and β values of 0.077 ± 0.18 μM, 3.3 ± 1.1 and 104 ± 56,
respectively. However, diverse effects of DES towards E2-3/17-O-glucuronidation
are not observed in liver microsomes from several common experimental animals.
In summary, this study issues new potential toxic mechanisms for DES: potently
inhibiting the activity of UGT1A1 and powerfully accelerating the formation of
cholestatic E2-17-O-glucuronide by UGT1A4.
Dehydroepiandrosterone: A neuroactive steroid

Luboslav Stárka, Michaela Dusková, Martin Hill
Journal of Steroid Biochemistry & Molecular Biology 145 (2015) 254–260
http://dx.doi.org/10.1016/j.jsbmb.2014.03.008

Dehydroepiandrosterone (DHEA) and its sulfate bound form (DHEAS) are important
steroids of mainly adrenal origin. They are produced also in gonads and in the brain.
Dehydroepiandrosterone easily crosses the brain–blood barrier and in part is also
produced locally in the brain tissue. In the brain, DHEA exerts its effects after
conversion to either testosterone and dihydrotestosterone or estradiol via androgen
and estrogen receptors present in the most parts of the human brain, through
mainly non-genomic mechanisms, or eventually indirectly via the effects of its
metabolites formed locally in the brain. As a neuroactive hormone, DHEA in
cooperation with other hormones and transmitters significantly affects some
aspects of human mood, and modifies some features of human emotions and
behavior. It has been reported that its administration can increase feelings of well-
being and is useful in ameliorating atypical depressive disorders. It has
neuroprotective and antiglucocorticoid activity and modifies immune reactions,
and some authors have also reported its role in degenerative brain diseases.
Here we present a short overview of the possible actions of dehydroepiandrosterone
and its sulfate in the brain, calling attention to various mechanisms of their action
as neurosteroids and to prospects for the knowledge of their role in brain disorders.
Androgens and mammalian male reproductive tract development

Aki Murashima, Satoshi Kishigami, Axel Thomson, Gen Yamada
Biochimica et Biophysica Acta 1849 (2015) 163–170
http://dx.doi.org/10.1016/j.bbagrm.2014.05.020

One of the main functions of androgen is in the sexually dimorphic development of
the male reproductive tissues. During embryogenesis, androgen determines the
morphogenesis of male specific organs, such as the epididymis, seminal vesicle,
prostate and penis. Despite the critical function of androgens in masculinization,
the downstream molecular mechanisms of androgen signaling are poorly
understood. Tissue recombination experiments and tissue specific androgen
receptor (AR) knockout mouse studies have revealed epithelial or mesenchymal
specific androgen-AR signaling functions. These findings also indicate that
epithelial–mesenchymal interactions are a key feature of AR specific activity,
and paracrine growth factor action may mediate some of the effects of androgens.
This review focuses on mouse models showing the interactions of androgen and
growth factor pathways that promote the sexual differentiation of reproductive organs.
Recent studies investigating context dependent AR target genes are also discussed.
This article is part of a Special Issue entitled: Nuclear receptors in animal development.

All sex steroids are made intracellularly in peripheral tissues by the mechanisms of
intracrinology after menopause

Fernand Labrie
Journal of Steroid Biochemistry & Molecular Biology 145 (2015) 133–138
http://dx.doi.org/10.1016/j.jsbmb.2014.06.001

Following the arrest of estradiol secretion by the ovaries at menopause, all estrogens
and all androgens in postmenopausal women are made locally in peripheral target
tissues according to the physiological mechanisms of intracrinology. The locally
made sex steroids exert their action and are inactivated intracellularly without
biologically significant release of the active sex steroids in the circulation.The
level of expression of the steroid-forming and steroid-inactivating enzymes is
specific to each cell type in each tissue, thus permitting to each cell/tissue to
synthesize a small amount of androgens and/or estrogens in order to meet the
local physiological needs without affecting the other tissues of the organism.
Achieved after 500 million years of evolution, combination of the arrest of ovarian
estrogen secretion, the availability of high circulating levels of DHEA and the
expression of the peripheral sex steroid-forming enzymes have permitted the
appearance of menopause with a continuing access to intra-tissular sex steroids
for the individual cells/tissues without systemic exposure to circulating estradiol.
In fact, one essential condition of menopause is to maintain serum estradiol at
biologically inactive (subthreshold) concentrations, thus avoiding stimulation of the
endometrium and risk of endometrial cancer. Measurement of the low levels of
serum estrogens and androgens in postmenopausal women absolutely requires
the use of MS/MS-based technology in order to obtain reliable accurate, specific
and precise assays. While the activity of the series of steroidogenic enzymes can
vary, the serum levels of DHEA show large individual variations going from barely
detectable to practically normal “premenopausal” values, thus explaining the
absence of menopausal symptoms in about 25% of women. It should be added
that the intracrine system has no feedback elements to adjust the serum levels
of DHEA, thus meaning that women with low DHEA activity will not be improved
without external supplementation. Exogenous DHEA, however, follows the same
intracrine rules as described for endogenous DHEA, thus maintaining serum
estrogen levels at subthreshold or biologically inactive concentrations. Such blood
concentrations are not different from those observed in normal postmenopausal
women having high serum DHEA concentrations. Androgens, on the other hand,
are practically all made intracellularly from DHEA by the mechanisms of intracrinology
and are always maintained at very low levels in the blood in both pre- and
postmenopausal women. Proof of the importance of intracrinology is also provided,
among others, by the well-recognized benefits of aromatase inhibitors and
anti-estrogens used successfully for the treatment of breast cancer in
postmenopausal women where all estrogens are made locally. Each medical
indication for the use of DHEA, however, requires clinical trials performed
according to the FDA guidelines and the best rules of clinical medicine.
A multi-step, dynamic allosteric model of testosterone’s binding to sex hormone
binding globulin

Mikhail N. Zakharov, Shalender Bhasin, Thomas G. Travison, Ran Xue, et al.
Molecular and Cellular Endocrinology 399 (2015) 190–200
http://dx.doi.org/10.1016/j.mce.2014.09.001

Purpose: Circulating free testosterone (FT) levels have been used widely in the
diagnosis and treatment of hypogonadism in men. Due to experimental
complexities in FT measurements, the Endocrine Society has recommended
the use of calculated FT (cFT) as an appropriate approach for estimating FT.
We show here that the prevailing model of testosterone’s binding to SHBG,
which assumes that each SHBG dimer binds two testosterone molecules
and that the two binding sites on SHBG have similar binding affinity is
erroneous and provides FT values that differ substantially from those
obtained using equilibrium dialysis.
Methods: We characterized testosterone’s binding to SHBG using
binding isotherms, ligand depletion curves, and isothermal titration
calorimetry (ITC). We derived a new model of testosterone’s binding to
SHBG from these experimental data and used this model to determine
FT concentrations and compare these values with those derived from
equilibrium dialysis.
Results: Experimental data on testosterone’s association with SHBG
generated using binding isotherms including equilibrium binding, ligand
depletion experiments, and ITC provide evidence of a multi-step dynamic
process, encompassing at least two inter-converting microstates in unliganded
SHBG, readjustment of equilibria between unliganded states upon binding
of the first ligand molecule, and allosteric interaction between two binding
sites of SHBG dimer. FT concentrations in men determined using the new
multistep dynamic model with complex allostery did not differ from those
measured using equilibrium dialysis. Systematic error in calculated FT
vales in females using Vermeulen’s model was also significantly reduced.
In European Male Aging Study, the men deemed to have low FT (<2.5th
percentile) by the new model were at increased risk of sexual symptoms
and elevated LH.
Conclusion: Testosterone’s binding to SHBG is a multi-step dynamic
process that involves complex allostery within SHBG dimer. FT values
obtained using the new model have close correspondence with those
measured using equilibrium dialysis.

Cohesin modulates transcription of estrogen-responsive genes

Jisha Antony, Tanushree Dasgupta, Jenny M. Rhodes, Miranda V. McEwan, et al.
Biochimica et Biophysica Acta 1849 (2015) 257–269
http://dx.doi.org/10.1016/j.bbagrm.2014.12.011

The cohesin complex has essential roles in cell division, DNA damage repair
and gene transcription. The transcriptional function of cohesin is thought to
derive from its ability to connect distant regulatory elements with gene promoters.
Genome-wide binding of cohesin in breast cancer cells frequently coincides
with estrogen receptor alpha (ERα), leading to the hypothesis that cohesin
facilitates estrogen-dependent gene transcription. We found that cohesin
modulates the expression of only a subset of genes in the ER transcription
program, either activating or repressing transcription depending on the gene
target. Estrogen-responsive genes most significantly influenced by cohesin
were enriched in pathways associated with breast cancer progression such
as PI3K and ErbB1. In MCF7 breast cancer cells, cohesin depletion enhanced
transcription of TFF1 and TFF2, and was associated with increased ER binding
and increased interaction between TFF1 and its distal enhancer situated
within TMPRSS3. In contrast, cohesin depletion reduced c-MYC mRNA and
was accompanied by reduced interaction between a distal enhancer of c-MYC
and its promoters. Our data indicates that cohesin is not a universal facilitator
of ER-induced transcription and can even restrict enhancer–promoter communication.
We propose that cohesion modulates transcription of estrogen-dependent genes
to achieve appropriate directionality and amplitude of expression.
Angiogenesis in Breast Cancer and its Correlation with Estrogen, Progesterone
Receptors and other Prognostic Factors

Jyotsna Naresh Bharti, Poonam Rani, Vinay Kamal, Prem Narayan Agarwal
Journal of Clinical and Diagnostic Research. 2015 Jan, Vol-9(1): EC05-EC07
http://dx.doi.org:/10.7860/JCDR/2015/10591.5447

Purpose: The  aim  of  study  is  to  evaluate  angiogenesis using  CD34,  in
estrogen,  progesterone  positive  and  negative breast cancer  and  to  correlate
the  microvessel  density  with known  histological  prognostic  factors,
morphological  type  of breast carcinoma and lymph node metastasis.
Materials and Methods: Twenty eight untreated cases of breast cancer were
included  in  the  study  and  paraffin  embedded  sections  were  obtained
from  representative  mastectomy specimen of breast cancer patient. The sections
were stained with hematoxylin and eosin stain and immunohistochemistry was
performed using CD34, estrogen, progesterone, cytokeratin and epithelial
membrane antigen  antibody.  Angiogenesis was analyzed using CD 34 antibody.
For statistical analysis, cases were grouped into estrogen, progesterone positive
and negative receptors.
Results: Mean microvessel density in ER-/PR-, ER-/ PR+, ER+/PR-, ER+/PR+
was 15.45, 14.83, 11, 10.89 respectively.  A significant correlation was found
between ER receptors and mean vascular density with p-value (< 0.05).
A significant difference was observed in mean vascular density between
the four groups comprising (p-value < 0.05).  Infiltrating duct carcinoma
(NOS) grade III has got the highest mean microvessel density (14.17)
followed by grade II (12.93) and grade I (12.33).
Conclusion: Information about prognostic factors in breast cancer
patients may lead to better ways to identify those patients at high risk
who might benefit from adjuvant therapies.

Combined blockade of testicular and locally made androgens in prostate cancer:
A highly significant medical progress based upon intracrinology

Fernand Labrie
Journal of Steroid Biochemistry & Molecular Biology 145 (2015) 144–156
http://dx.doi.org/10.1016/j.jsbmb.2014.05.012

Recently two drugs, namely the antiandrogen MDV-3100 and the inhibitor
of 17β-hydroxylase abiraterone have been accepted by the FDA for the
treatment of castration-resistant prostate cancer (CRPC) with or without
previous chemotherapy, with a prolongation of overall survival of 2.2–4.8months.
While medical (GnRH agonist) or surgical castration reduces the serum levels
of testosterone by about 97%, an important concentration of testosterone and
dihydrotestosterone remains in the prostate and activates the androgen receptor
(AR), thus offering an explanation for the positive data obtained in CRPC. In fact,
explanation of the response observed with MDV-3100 or enzalutamide in CRPC
is essentially a blockade of the action or formation of intraprostatic androgens.
In addition to the inhibition of the action or formation of androgens made locally
by the mechanisms of intracrinology, increased AR levels and AR mutations can
be involved, especially in very advanced disease.

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EARLY DETECTION OF PROSTATE CANCER: AUA GUIDELINE

Author-Writer: Dror Nir, PhD

 

 When reviewing the DETECTION OF PROSTATE CANCER section on the AUA website , The first thing that catches one’s attention is the image below; clearly showing two “guys” exploring with interest what could be a CT or MRI image…..

 fig 1

But, if you bother to read the review underneath this image regarding EARLY DETECTION OF PROSTATE CANCER: AUA GUIDELINE produced by an independent group that was commissioned by the AUA to conduct a systematic review and meta-analysis of the published literature on prostate cancer detection and screening; Panel Members: H. Ballentine Carter, Peter C. Albertsen, Michael J. Barry, Ruth Etzioni, Stephen J. Freedland, Kirsten Lynn Greene, Lars Holmberg, Philip Kantoff, Badrinath R. Konety, Mohammad Hassan Murad, David F. Penson and Anthony L. Zietman – You are bound to be left with a strong feeling that something is wrong!

The above mentioned literature review was done using rigorous approach.

“The AUA commissioned an independent group to conduct a systematic review and meta-analysis of the published literature on prostate cancer detection and screening. The protocol of the systematic review was developed a priori by the expert panel. The search strategy was developed and executed

by reference librarians and methodologists and spanned across multiple databases including Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Database of Systematic Reviews, Ovid Cochrane Central Register of Controlled Trials and Scopus. Controlled vocabulary supplemented with keywords was used to search for the relevant concepts of prostate cancer, screening and detection. The search focused on DRE, serum biomarkers (PSA, PSA Isoforms, PSA kinetics, free PSA, complexed PSA, proPSA, prostate health index, PSA velocity, PSA

doubling time), urine biomarkers (PCA3, TMPRSS2:ERG fusion), imaging (TRUS, MRI, MRS, MR-TRUS fusion), genetics (SNPs), shared-decision making and prostate biopsy. The expert panel manually identified additional references that met the same search criteria”

While reading through the document, I was looking for the findings related to the roll of imaging in prostate cancer screening; see highlighted above. The only thing I found: “With the exception of prostate-specific antigen (PSA)-based prostate cancer screening, there was minimal evidence to assess the outcomes of interest for other tests.

This must mean that: Notwithstanding hundreds of men-years and tens of millions of dollars which were invested in studies aiming to assess the contribution of imaging to prostate cancer management, no convincing evidence to include imaging in the screening progress was found by a group of top-experts in a thorough and rigorously managed literature survey! And it actually  lead the AUA to declare that “Nothing new in the last 20 years”…..

My interpretation of this: It says-it-all on the quality of the clinical studies that were conducted during these years, aiming to develop an improved prostate cancer workflow based on imaging. I hope that whoever reads this post will agree that this is a point worth considering!

For those who do not want to bother reading the whole AUA guidelines document here is a peer reviewed summary:

Early Detection of Prostate Cancer: AUA Guideline; Carter HB, Albertsen PC, Barry MJ, Etzioni R, Freedland SJ, Greene KL, Holmberg L, Kantoff P, Konety BR, Murad MH, Penson DF, Zietman AL; Journal of Urology (May 2013)”

It says:

“A systematic review was conducted and summarized evidence derived from over 300 studies that addressed the predefined outcomes of interest (prostate cancer incidence/mortality, quality of life, diagnostic accuracy and harms of testing). In addition to the quality of evidence, the panel considered values and preferences expressed in a clinical setting (patient-physician dyad) rather than having a public health perspective. Guideline statements were organized by age group in years (age<40; 40 to 54; 55 to 69; ≥70).

RESULTS: With the exception of prostate-specific antigen (PSA)-based prostate cancer screening, there was minimal evidence to assess the outcomes of interest for other tests. The quality of evidence for the benefits of screening was moderate, and evidence for harm was high for men age 55 to 69 years. For men outside this age range, evidence was lacking for benefit, but the harms of screening, including over diagnosis and over treatment, remained. Modeled data suggested that a screening interval of two years or more may be preferred to reduce the harms of screening.

CONCLUSIONS: The Panel recommended shared decision-making for men age 55 to 69 years considering PSA-based screening, a target age group for whom benefits may outweigh harms. Outside this age range, PSA-based screening as a routine could not be recommended based on the available evidence. The entire guideline is available at www.AUAnet.org/education/guidelines/prostate-cancer-detection.cfm.”

Other research papers related to the management of Prostate cancer were published on this Scientific Web site:

From AUA2013: “Histoscanning”- aided template biopsies for patients with previous negative TRUS biopsies

Imaging-biomarkers is Imaging-based tissue characterization

On the road to improve prostate biopsy

State of the art in oncologic imaging of Prostate

Imaging agent to detect Prostate cancer-now a reality

Scientists use natural agents for prostate cancer bone metastasis treatment

Today’s fundamental challenge in Prostate cancer screening

ROLE OF VIRAL INFECTION IN PROSTATE CANCER

Men With Prostate Cancer More Likely to Die from Other Causes

New Prostate Cancer Screening Guidelines Face a Tough Sell, Study Suggests

New clinical results supports Imaging-guidance for targeted prostate biopsy

Prostate Cancer: Androgen-driven “Pathomechanism” in Early-onset Forms of the Disease

Prostate Cancer and Nanotecnology

Prostate Cancer Cells: Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition

Imaging agent to detect Prostate cancer-now a reality

Scientists use natural agents for prostate cancer bone metastasis treatment

ROLE OF VIRAL INFECTION IN PROSTATE CANCER

Prostate Cancers Plunged After USPSTF Guidance, Will It Happen Again?

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Reporter: Aviva Lev-Ari, PhD, RN

Dr. Lev-Ari was Director @ SRI International in the mid 1980s.

Denong Wang

Distinguished Scientist and Senior Program Director, Tumor Glycomics Laboratory, Center for Cancer and Metabolism
Denong Wang

Denong Wang, Ph.D., is an SRI distinguished scientist and senior program director of the Tumor Glycome Laboratoryin the Center for Cancer and Metabolism in SRI Biosciences. Wang’s long-term research interest is in the carbohydrate moieties that are critical for self/non-self recognition and induction of antibody responses.

Wang’s team has established multiple platforms of carbohydrate microarrays and introduced these glycomics tools to explore the structural and antigenic diversities of the glycome. The main research focus of his lab is in the immunogenic sugar moieties. In the past few years, his group has contributed to the identification of immunologically potent glycan markers of SARS-CoV, Bacillus anthracis exosporium, and a number of human cancers.

Wang received his Ph.D. in immunology and glycobiology with the late Professor Elvin A. Kabat at Columbia University in 1993. After that, he entered the developing field of post-genomics research. Before joining SRI in 2010, he served as head of the Functional Genomics Division at Columbia University’s Genome Center from 1998 to 2003 and was director of Stanford University’s Tumor Glycome Laboratory from 2007 to 2010.

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A Blood Test to Identify Aggressive Prostate Cancer

By Denong Wang at 9:15 AM PDT, Wed May 8, 2013

tumor glycomicsProstate cancer is the second most common cancer in American men, killing nearly 30,000 per year. In 2004, I attended a conference where one of the nation’s leading researchers in the field declared that the gold-standard test for this disease was not successful at identifying dangerous invasive tumors. That triggered my interest in how to address the challenge of developing a blood test to detect the deadly form of prostate cancer.

After nearly a decade, my collaborators and I have found the first marker that specifically identifies the approximately six to eight percent of prostate cancers that are considered “aggressive,” meaning they will migrate to other parts of the body, at which point they are very difficult to treat. Although we have confirmed this marker, there is much to be done before a clinical application can be developed.

If further study confirms that the test is clinically reliable, it can provide a much-needed tool to differentiate between aggressive cancer and the majority of cases, which are slow-growing tumors with a low probability of migrating to other parts of the body (and thus don’t require special treatment, such as radical prostatectomy).

The current standard test looks at elevated blood prostate-specific antigen (PSA) levels, known as the PSA test. Dr. Thomas Stamey, an emeritus faculty member and urologist at the Stanford University School of Medicine, published his original findings in 1987 linking elevated blood PSA levels to prostate cancer. In 2004, Dr. Stamey declared that the PSA test was no longer useful for the diagnosis of prostate cancer. Rather, an elevated PSA level is now known to reflect the volume increase of a prostate, which could either be associated with a harmless increase in prostate size called benign prostatic hyperplasia (BPH), or be caused by cancer.

I began collaborating with Dr. Stamey and his Stanford colleague Dr. Donna Peehl to look for a new prostate cancer marker, hopefully one that would indicate the presence of aggressive prostate cancer through a blood test.  This is a very active area of research, with scientists exploring the idea from (1) a genomics perspective, (2) a proteomics perspective, and (3) a glycomics perspective, the latter of which entails using carbohydrate-based markers to identify cancer. My focus is the third area, where we are concentrating on how the immune system recognizes changes in the carbohydrates found on the surface of cancer cells compared with those on the surface of normal cells.  

SRI’s Tumor Glycome Laboratory has discovered a marker that appears to be associated with aggressive prostate cancer. The marker is an antibody that is produced against a carbohydrate molecule on the surface of aggressive prostate cancer cells, and is expressed in increasing levels that correlate with cancer severity. We call it a “cryptic” biomarker, since it only becomes an immunological target if something goes awry in the cell, such as a viral infection or the malignant transformation of normal cells to cancer.

This biomarker has the potential, with further development, to be used as a test to help diagnose aggressive prostate cancer. It is rewarding to have reached this point in our understanding of prostate cancer and toward a diagnostic test that ultimately could save lives.

Our research findings were published last year in the Journal of Proteomics & Bioinformatics (5:090-095, DOI:10.4172/jpb.1000218). Our latest study, published in Drug Development Research, lays the foundation for predicting which prostate cancer patients may develop more aggressive forms of the disease and directs the future design of more effective treatments [14(2):65-80, DOI: 10.1002/ddr.21063].

Anti‐Oligomannose Antibodies as Potential Serum Biomarkers of Aggressive Prostate Cancer

Abstract

This study bridges a carbohydrate microarray discovery and a large‐scale serological validation of anti‐oligomannose antibodies as novel serum biomarkers of aggressive prostate cancer (PCa). Experimentally, a Man9‐cluster‐specific enzyme‐linked immunosorbent assay was established to enable sensitive detection of anti‐Man9 antibodies in human sera. A large‐cohort of men with PCa or benign prostatic hyperplasia (BPH) whose sera were banked at Stanford University was characterized using this assay. Subjects included patients with 100% Gleason grade 3 cancer (n = 84), with Gleason grades 4 and/or 5 cancer (n = 204), and BPH controls (n = 135). Radical prostatectomy Gleason grades and biochemical (PSA) recurrence served as key parameters for serum biomarker evaluation. It was found that IgGMan9 and IgMMan9 were widely present in the sera of men with BPH, as well as those with cancer. However, these antibody reactivities were significantly increased in the subjects with the largest volumes of high grade cancer. Detection of serum IgGMan9 and IgMMan9 significantly predicted the clinical outcome of PCa post‐radical prostatectomy. Given these results, we suggest that IgGMan9 and IgMMan9 are novel serum biomarkers for monitoring aggressive progression of PCa. The potential of oligomannosyl antigens as targets for PCa subtyping and targeted immunotherapy is yet to be explored.

Authors: Denong Wang, Laila Dafik, Rosalie Nolley, Wei Huang, Russell D. Wolfinger, Lai‐Xi Wang, Donna M. Peehl
Journal: Drug Development Research
Year: 2013
Pages: n/a
DOI: 10.1002/ddr.21063
Publication date: 11-02-2013

Proteomics & Bioinformatics

N-glycan Cryptic Antigens as Active Immunological Targets in Prostate

Cancer Patients

Denong Wang*

Tumor Glycomics Laboratory, Center for Cancer Research, Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA

*Corresponding author: Dr. Denong Wang, Tumor Glycomics Laboratory,

Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo

Park, CA 94025, USA, Tel: +1 650 859-2789; Fax: +1 650 859-3153; E-mail:

denong.wang@sri.com

Received March 07, 2012; Accepted April 13, 2012; Published April 30, 2012

Citation: Wang D (2012) N-glycan Cryptic Antigens as Active Immunological

Targets in Prostate Cancer Patients. J Proteomics Bioinform 5: 090-095.

doi:10.4172/jpb.1000218

Copyright: © 2012 Wang D.

Abstract

Although tumor-associated abnormal glycosylation has been recognized for decades, information regarding host recognition of the evolving tumor glycome remains elusive. We report here a carbohydrate microarray analysis of a number of tumor-associated carbohydrates for their serum antibody reactivities and potential immunogenicity in humans. These are the precursors, cores and internal sequences of N-glycans. They are usually masked by other sugar moieties and belong to a class of glyco-antigens that are normally “cryptic”. However, viral expression of these carbohydrates may trigger host immune responses. For examples, HIV-1 and SARS-CoV display Man9 clusters and tri- or multi-antennary type II (Galβ1→4GlcNAc) chains (Tri/m-II), respectively; viral neutralizing antibodies often target these sugar moieties. We asked, therefore, whether prostate tumor expression of corresponding carbohydrates triggers antibody responses in vivo. Using carbohydrate microarrays, we analyzed a panel of human sera, including 17 samples from prostate cancer patients and 12 from men with Benign Prostatic Hyperplasia (BPH).

We observed that IgG antibodies targeting the Man9- or Tri-/m-II-autoantigens are readily detectable in the sera of men with BPH, as well as those with cancer. Importantly, these antibody activities were selectively increased in prostate cancer patients. Thus, human immune systems actively recognize these N-glycan cryptic carbohydrates and produce targeting antibodies. This finding shads a light on a class of previously less studied immunological targets of human cancers. Identifying the diagnostic, prognostic and therapeutic values of these targets will require further investigation.

http://www.omicsonline.org/0974-276X/JPB-05-090.pdf

 

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Author, Curator: Tilda Barliya, PhD

Prostate cancer  is common and a frequent cause of cancer death. In the United States, prostate cancer is the most commonly diagnosed visceral cancer. In 2012, there were expected to be about 242,000 new prostate cancer diagnoses and about 28,000 prostate cancer deaths. Prostate cancer is second only to nonmelanoma skin cancer and lung cancer as the leading cause of cancer and cancer death, respectively, in US men. Worldwide, in 2008 there were estimated to be 903,000 new cases of prostate cancer and 258,000 prostate cancer deaths making it the second most commonly diagnosed cancer in men and the sixth leading cause of male cancer death (1).

Prostate cancer survival is related to many factors, especially the extent of tumor at the time of diagnosis. The five-year relative survival among men with cancer confined to the prostate (localized) or with just regional spread is 100 percent compared with 31.9 percent among those diagnosed with distant metastases . While men with advanced stage disease may benefit from palliative treatment, their tumors are generally not curable

Prostate-specific antigen (PSA) testing revolutionized prostate cancer screening. Although PSA was originally introduced as a tumor marker to detect cancer recurrence or disease progression following treatment, it became widely adopted for cancer screening by the early 1990s. Subsequently, professional societies issued guidelines supporting prostate cancer screening with PSA. PSA testing led to a dramatic increase in the incidence of prostate cancer, the majority of these newly-diagnosed cancers were clinically localized which led to an increase in radical prostatectomy and radiation therapy, aggressive treatments intended to cure these early-stage cancers (2). However, PSA is also elevated in a number of benign conditions, particularly benign prostatic hyperplasia (BPH) and prostatitis

So what is PSA?

PROSTATE SPECIFIC ANTIGEN (PSA) — PSA is a glycoprotein produced by prostate epithelial cells. PSA levels may be elevated in men with prostate cancer because PSA production is increased and because tissue barriers between the prostate gland lumen and the capillary are disrupted, releasing more PSA into the serum.

A research team led by Prof. Langer and Prof. Farokhzad from MIT and and Brigham and Women’s Hospital in Boston have developed a nanotechnology strategies adopted for the management of prostate cancer. In particular, the combination of targeted and controlled-release polymer nanotechnologies has recently resulted in the clinical development of BIND-14, a promising targeted Docetaxel-loaded nanoprototype, which can be validated for use in the prostate cancer therapy and entered clinical trials in January 2011

The BIND-014 nanoparticles have three components: one that carries the drug (docetaxel), one that targets PSMA, and one that helps evade macrophages and other immune-system cells.

Clinical results

The Phase I clinical trial involved 17 patients with advanced or metastatic tumors who had already gone through traditional chemotherapy. In Phase I trials, researchers evaluate a potential drug’s safety and study its effects in the body. To determine safe dosages, patients were given escalating doses of the nanoparticles. So far, doses of BIND-014 have reached the amount of docetaxel usually given without nanoparticles, with no new side effects. The known side effects of docetaxel have also been milder.

In the 48 hours after treatment, the researchers found that docetaxel concentration in the patients’ blood was 100 times higher with the nanoparticles as compared to docetaxel administered in its conventional form. Higher blood concentration of BIND-014 facilitated tumor targeting resulting in tumor shrinkage in patients, in some cases with doses of BIND-014 that correspond to as low as 20 percent of the amount of docetaxel normally given. The nanoparticles were also effective in cancers in which docetaxel usually has little activity, including cervical cancer and cancer of the bile ducts.

Summary:

Early detection of prostate cancer increased dramatically the five-year survival of patients. “This study demonstrates for the first time that it is possible to generate medicines with both targeted and programmable properties that can concentrate the therapeutic effect directly at the site of disease, potentially revolutionizing how complex diseases such as cancer are treated”. The Phase I clinical trial is still ongoing and continued dose escalation is underway; BIND Biosciences is now planning Phase II trials, which will further investigate the treatment’s effectiveness in a larger number of patients.

REFERENCES

1. Richard M Hoffman. Screening for prostate cancer. http://www.uptodate.com/contents/screening-for-prostate-cancer

2. http://web.mit.edu/newsoffice/2012/cancer-particle-0404.html

3. http://www.bindbio.com/content/pages/news/news_detail.jsp/q/news-id/70

4. State of the art in oncologic imaging of Prostate

https://pharmaceuticalintelligence.com/2013/01/28/state-of-the-art-in-oncologic-imaging-of-prostate/

 

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Last week, I came across an interesting abstract related to work that is carried-out in UCLA for several years now by Prof. Lenny Marks. Lenny participated to the development of “Artemis”. Artemis is a system that is adjunct to ultrasound and performs 3D Imaging and Navigation for Prostate Biopsy by Eigen. I thought that this deserves a complementary post to Imaging-guided biopsies: Is there a preferred strategy to choose? which I posted few weeks ago

Artemis

When men present with risk parameters for harboring prostate cancer, they are advised to undergo a transrectal ultrasound guided prostate biopsy (TRUS biopsy). Over one million biopsies are carried out in the USA ever year.

The indications for a prostate biopsy in the USA are:

·         Raised PSA above 2.5ng/ml

·         Raised age-specific PSA

·         Family history of prostate cancer

·         High PSA density > 0.15ng/ml/cc

·         High PSA velocity> 0.75 ng/ml/year or doubling time ❤ years

·         Abnormal digital rectal examination

Overall, men undergoing systematic trans-rectal ultrasound (TRUS) guided biopsy of 12 cores of prostatic tissue have approximately 1 in 4 probability of being diagnosed with prostate cancer. Of these, about half are diagnosed with low risk disease. A known problem with the current practice of TRUS biopsy, is that it is performed blind – the operator does not know where the cancer is. Therefore, many low risk cancers that do not need treating are detected and many high risk cancers are missed or incorrectly classified.

The abstract below is reporting the results of a clinical study, aimed to evaluate the potential added value in using Artemis and ultrasound-MRI image fusion when performing TRUS biopsies, as a method and system to allow urologists to progress from blind biopsies to biopsies, which are mapped, targeted and tracked.

Image fusion is the process of combining multiple images from various sources into a single representative image. Ultrasound is the imaging modality used to guide Artemis in performing the biopsies. In this study MRI is used to overcome the “blindness” regarding tumor location. More on MRI’s cancer detection reliability  can be found in my posts Imaging-guided biopsies: Is there a preferred strategy to choose? and Today’s fundamental challenge in Prostate cancer screening.

Source

Curr Opin Urol. 2013 Jan;23(1):43-50. doi: 10.1097/MOU.0b013e32835ad3ee.

MRI-ultrasound fusion for guidance of targeted prostate biopsy.

Marks LYoung SNatarajan S.  Department of Urology, David Geffen School of Medicine bCenter for Advanced Surgical and Interventional Technology, University of California, Los Angeles, Los Angeles, California, USA.

Abstract

PURPOSE OF REVIEW:

Prostate cancer (CaP) may be detected on MRI. Fusion of MRI with ultrasound allows urologists to progress from blind, systematic biopsies to biopsies, which are mapped, targeted and tracked. We herein review the current status of prostate biopsy via MRI/ultrasound fusion.

RECENT FINDINGS:

Three methods of fusing MRI for targeted biopsy have been recently described: MRI-ultrasound fusion, MRI-MRI fusion (‘in-bore’ biopsy) and cognitive fusion. Supportive data are emerging for the fusion devices, two of which received US Food and Drug Administration approval in the past 5 years: Artemis (Eigen, USA) and Urostation (Koelis, France). Working with the Artemis device in more than 600 individuals, we found that targeted biopsies are two to three times more sensitive for detection of CaP than nontargeted systematic biopsies; nearly 40% of men with Gleason score of at least 7 CaP are diagnosed only by targeted biopsy; nearly 100% of men with highly suspicious MRI lesions are diagnosed with CaP; ability to return to a prior biopsy site is highly accurate (within 1.2 ± 1.1 mm); and targeted and systematic biopsies are twice as accurate as systematic biopsies alone in predicting whole-organ disease.

SUMMARY:

In the future, MRI-ultrasound fusion for lesion targeting is likely to result in fewer and more accurate prostate biopsies than the present use of systematic biopsies with ultrasound guidance alone.

Written by: Dror Nir, PhD.

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The unfortunate ending of the Tower of Babel construction project and its effect on modern imaging-based cancer patients’ management


The story of the city of Babel is recorded in the book of Genesis 11 1-9. At that time, everyone on earth spoke the same language.

Picture: Pieter Bruegel the Elder: The Tower of Babel_(Vienna)

It is probably safe to assume that medical practitioners at that time were reporting the status of their patients in a standard manner. Although not mentioned, one might imagine that, at that time, ultrasound or MRI scans were also reported in a standard and transferrable manner. The people of Babel noticed the potential in uniform communication and tried to build a tower so high that it would  reach the gods. Unfortunately, God did not like that, so he went down (in person) and confounded people’s speech, so that they could not understand each another. Genesis 11:7–8.

This must be the explanation for our inability to come to a consensus on reporting of patients’ imaging-outcome. Progress in development of efficient imaging protocols and in clinical management of patients is withheld due to high variability and subjectivity of clinicians’ approach to this issue.

Clearly, a justification could be found for not reaching a consensus on imaging protocols: since the way imaging is performed affects the outcome, (i.e. the image and its interpretation) it takes a long process of trial-and-error to come up with the best protocol.  But, one might wonder, wouldn’t the search for the ultimate protocol converge faster if all practitioners around the world, who are conducting hundreds of clinical studies related to imaging-based management of cancer patients, report their results in a standardized and comparable manner?

Is there a reason for not reaching a consensus on imaging reporting? And I’m not referring only to intra-modality consensus, e.g. standardizing all MRI reports. I’m referring also to inter-modality consensus to enable comparison and matching of reports generated from scans of the same organ by different modalities, e.g. MRI, CT and ultrasound.

As developer of new imaging-based technologies, my personal contribution to promoting standardized and objective reporting was the implementation of preset reporting as part of the prostate-HistoScanning product design. For use-cases, as demonstrated below, in which prostate cancer patients were also scanned by MRI a dedicated reporting scheme enabled matching of the HistoScanning scan results with the prostate’s MRI results.

The MRI reporting scheme used as a reference is one of the schemes offered in a report by Miss Louise Dickinson on the following European consensus meeting : Magnetic Resonance Imaging for the Detection, Localisation, and Characterisation of Prostate Cancer: Recommendations from a European Consensus Meeting, Louise Dickinson a,b,c,*, Hashim U. Ahmed a,b, Clare Allen d, Jelle O. Barentsz e, Brendan Careyf, Jurgen J. Futterer e, Stijn W. Heijmink e, Peter J. Hoskin g, Alex Kirkham d, Anwar R. Padhani h, Raj Persad i, Philippe Puech j, Shonit Punwani d, Aslam S. Sohaib k, Bertrand Tomball,Arnauld Villers m, Jan van der Meulen c,n, Mark Emberton a,b,c,

http://www.europeanurology.com/article/S0302-2838(10)01187-5

Image of MRI reporting scheme taken from the report by Miss Louise Dickinson

The corresponding HistoScanning report is following the same prostate segmentation and the same analysis plans:


Preset reporting enabling matching of HistoScanning and MRI reporting of the same case.

It is my wish that already in the near-future, the main radiology societies (RSNA, ESR, etc..) will join together to build the clinical Imaging’s “Tower of Babel” to effectively address the issue of standardizing reporting of imaging procedures. This time it will not be destroyed…:-)

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Knowing the tumor’s size and location, could we target treatment to THE ROI by applying imaging-guided intervention?


Knowing the tumor’s size and location, could we target treatment to THE ROI by applying imaging-guided intervention?

Author: Dror Nir, PhD

 

Advances in techniques for cancer lesions’ detection and localisation [1-6] opened the road to methods of localised (“focused”) cancer treatment [7-10].  An obvious challenge on the road is reassuring that the imaging-guided treatment device indeed treats the region of interest and preferably, only it.

A step in that direction was taken by a group of investigators from Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada who evaluate the feasibility and safety of magnetic resonance (MR) imaging–controlled transurethral ultrasound therapy for prostate cancer in humans [7]. Their study’s objective was to prove that using real-time MRI guidance of HIFU treatment is possible and it guarantees that the location of ablated tissue indeed corresponds to the locations planned for treatment. Eight eligible patients were recruited.

 

The setup

 

Treatment protocol

 

The result

 

“There was excellent agreement between the zone targeted for treatment and the zone of thermal injury, with a targeting accuracy of ±2.6 mm. In addition, the temporal evolution of heating was very consistent across all patients, in part because of the ability of the system to adapt to changes in perfusion or absorption properties according to the temperature measurements along the target boundary.”

 

Technological problems to be resolved in the future:

“Future device designs could incorporate urinary drainage during the procedure, given the accumulation of urine in the bladder during treatment.”

“Sufficient temperature resolution could be achieved only by using 10-mm-thick sections. Our numeric studies suggest that 5-mm-thick sections are necessary for optimal three-dimensional conformal heating and are achievable by using endorectal imaging coils or by performing the treatment with a 3.0-T platform.”

Major limitation: “One of the limitations of the study was the inability to evaluate the efficacy of this treatment; however, because this represents, to our knowledge, the first use of this technology in human prostate, feasibility and safety were emphasized. In addition, the ability to target the entire prostate gland was not assessed, again for safety considerations. We have not attempted to evaluate the effectiveness of this treatment for eradicating cancer or achieving durable biochemical non-evidence of disease status.”

References

  1. SIMMONS (L.A.M.), AUTIER (P.), ZATURA (F.), BRAECKMAN (J.G.), PELTIER (A.), ROMICS (I.), STENZL (A.), TREURNICHT (K.), WALKER (T.), NIR (D.), MOORE (C.M.), EMBERTON (M.). Detection, localisation and characterisation of prostate cancer by Prostate HistoScanning.. British Journal of Urology International (BJUI). Issue 1 (July). Vol. 110, Page(s): 28-35
  2. WILKINSON (L.S.), COLEMAN (C.), SKIPPAGE (P.), GIVEN-WILSON (R.), THOMAS (V.). Breast HistoScanning: The development of a novel technique to improve tissue characterization during breast ultrasound. European Congress of Radiology (ECR), A.4030, C-0596, 03-07/03/2011.
  3. Hebert Alberto Vargas, MD, Tobias Franiel, MD,Yousef Mazaheri, PhD, Junting Zheng, MS, Chaya Moskowitz, PhD, Kazuma Udo, MD, James Eastham, MD and Hedvig Hricak, MD, PhD, Dr(hc) Diffusion-weighted Endorectal MR Imaging at 3 T for Prostate Cancer: Tumor Detection and Assessment of Aggressiveness. June 2011 Radiology, 259,775-784.
  4. Wendie A. Berg, Kathleen S. Madsen, Kathy Schilling, Marie Tartar, Etta D. Pisano, Linda Hovanessian Larsen, Deepa Narayanan, Al Ozonoff, Joel P. Miller, and Judith E. Kalinyak Breast Cancer: Comparative Effectiveness of Positron Emission Mammography and MR Imaging in Presurgical Planning for the Ipsilateral Breast Radiology January 2011 258:1 59-72.
  5. Anwar R. Padhani, Dow-Mu Koh, and David J. Collins Reviews and Commentary – State of the Art: Whole-Body Diffusion-weighted MR Imaging in Cancer: Current Status and Research Directions Radiology December 2011 261:3 700-718
  6. Eggener S, Salomon G, Scardino PT, De la Rosette J, Polascik TJ, Brewster S. Focal therapy for prostate cancer: possibilities and limitations. Eur Urol 2010;58(1):57–64).
  7. Rajiv Chopra, PhD, Alexandra Colquhoun, MD, Mathieu Burtnyk, PhD, William A. N’djin, PhD, Ilya Kobelevskiy, MSc, Aaron Boyes, BSc, Kashif Siddiqui, MD, Harry Foster, MD, Linda Sugar, MD, Masoom A. Haider, MD, Michael Bronskill, PhD and Laurence Klotz, MD. MR Imaging–controlled Transurethral Ultrasound Therapy for Conformal Treatment of Prostate Tissue: Initial Feasibility in Humans. October 2012 Radiology, 265,303-313.
  8. Black, Peter McL. M.D., Ph.D.; Alexander, Eben III M.D.; Martin, Claudia M.D.; Moriarty, Thomas M.D., Ph.D.; Nabavi, Arya M.D.; Wong, Terence Z. M.D., Ph.D.; Schwartz, Richard B. M.D., Ph.D.; Jolesz, Ferenc M.D.  Craniotomy for Tumor Treatment in an Intraoperative Magnetic Resonance Imaging Unit. Neurosurgery: September 1999 – Volume 45 – Issue 3 – p 423
  9. Medel, Ricky MD,  Monteith, Stephen J. MD, Elias, W. Jeffrey MD, Eames, Matthew PhD, Snell, John PhD, Sheehan, Jason P. MD, PhD, Wintermark, Max MD, MAS, Jolesz, Ferenc A. MD, Kassell, Neal F. MD. Neurosurgery: Magnetic Resonance–Guided Focused Ultrasound Surgery: Part 2: A Review of Current and Future Applications. October 2012 – Volume 71 – Issue 4 – p 755–763
  10. Bruno Quesson PhD, Jacco A. de Zwart PhD, Chrit T.W. Moonen PhD. Magnetic resonance temperature imaging for guidance of thermotherapy. Journal of Magnetic Resonance Imaging, Special Issue: Interventional MRI, Part 1, Volume 12, Issue 4, pages 525–533, October 2000

Writer: Dror Nir, PhD

 

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