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Review
Protective Effects of Human Chorionic
Gonadotropin Against Breast Cancer:
How Can We Use This Information
to Prevent/Treat the Disease?
C. V. Rao, PhD1,2,3
Abstract
Breast cancers (BCs) are the most common malignancies among women worldwide. Giving birth to a first child before 24 years of
age decreases the BC risk by about half, when women reach menopausal years. The scientific evidence suggests that the actions of
human chorionic gonadotropin (hCG) are responsible for this decrease. Human BC cells and tissues contain hCG/luteinizing
hormone receptors. The activation of the receptors results in an increase in cell differentiation and apoptosis. Conversely, it
decreases the cell proliferation, invasion, and survival. The hCG actions are primarily cyclic adenosine monophosphate/protein
kinase A mediated, require the presence of receptors, and involve blocking the activation and nuclear translocation of the
transcription factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). The women with a higher hCG levels
during pregnancy tend to have a lower BC incidence and those with the receptor-positive tumors have a longer metastasis-free
survival. The long-term benefits of pregnancy/hCG seem to come from permanent signature genomic imprinting and expression
changes, which are characterized by low cell proliferation, increased efficiency of DNA repair mechanisms, cell differentiation, and
cells resistance to carcinogenesis. These findings could provide clinical opportunities to use hCG for the prevention of BC in this
modern era of increasing number of young women in our societies waiting longer than ever to have their first child. In addition,
hCG may be useful to reduce and/or eliminate cellular targets of carcinogenic changes during an active ongoing disease.
Keywords
breast cancer, prevention/treatment, hCG/LH receptors, paradigm shift, nongonadal actions, cell differentiation, human breast
cancer cells and xenografts, genomic imprinting
Introduction
Breast cancers (BCs) are the most common malignancies
among women worldwide.1-4
Their incidence is higher in
developed than in developing countries and greater in white
than in African American, Asian, Hispanic, and Pacific Islan-
der women.1-4
However, more black women are likely die from
the disease. The incidence also increases with age, thus, post-
menopausal women are more frequently diagnosed with this
malignancy.1-4
However, the tumors in older women are less
aggressive than in younger women. Most BCs are ductal car-
cinomas and they can be invasive, which are more frequent.1-4
It is estimated that about 246 000 new BC cases will be diag-
nosed and 40 450 will die from the disease during 2016.4
Cur-
rently, there are about 2.8 million BC survivors in the United
States alone.4
Early detection is a key to good prognosis and survival.4,5
The early signs of potential BC are self-palpable breast lumps,
which can be noncancerous.4,5
The definitive diagnosis can be
made by histopathological examination of core needle biop-
sies.4,5
Mammograms are the best screening tools for an early
detection of BCs. Deaths due to BC are decreasing due to an
early detection, discontinuation of the use of only estrogen-
containing oral contraceptive pills, and estrogen replacement
therapy for the control of menopausal symptoms and choosing
healthy lifestyles.4,5
Men can also get BC, but the incidence, as
1
Department of Cellular Biology and Pharmacology, Reproduction and
Development Program, Herbert Wertheim College of Medicine, Florida
International University, Miami, FL, USA
2
Department of Molecular and Human Genetics, Reproduction and Devel-
opment Program, Herbert Wertheim College of Medicine, Florida Interna-
tional University, Miami, FL, USA
3
Department of Obstetrics and Gynecology, Reproduction and Development
Program, Herbert Wertheim College of Medicine, Florida International Uni-
versity, Miami, FL, USA
Corresponding Author:
C. V. Rao, Departments of Cellular Biology and Pharmacology, Molecular and
Human Genetics and Obstetrics and Gynecology, Reproduction and Devel-
opment Program, Herbert Wertheim College of Medicine, Florida Interna-
tional University, Miami, FL 33199, USA.
Email: crao@fiu.edu
Reproductive Sciences
1-9
ª The Author(s) 2016
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well as deaths, are about 100 times lower than that in women.4,6
The BCs are associated with huge national and individual costs.
In addition, the affected individuals and their families and
friends go through emotional distress, anxiety, depression, and
so on.
Risk Factors for BC
There are many risk factors and having them does not neces-
sarily mean that the person will get the disease.4
For example,
most women have some risk factors, yet most of them do not
get BC.4
On the other hand, some women develop the disease
even though they do not seem to have any risk factors.4
Not all
the risk factors affect the disease to the same degree.4
Thus,
there is no broad-brush stroke to predict who might or might
not develop BC, despite the risk factors.
The risk factors fall into nonreproductive and reproductive
categories. Nonreproductive risk factors are age, individual and
family history of the disease, mutations in tumor suppressor
genes, such as BRAC1, BRAC2, and others, radiation therapy
of the breast and chest, postmenopausal obesity, an excess
alcohol consumption, and so on.4,5
About 5% to 10% of the
BC cases are due to heredity.4
The reproductive risk factors include early menarche, late
menopause, never have given childbirth (nulliparous), giving
first childbirth at 35 years of age or later, long-term use of only
estrogen-containing oral contraceptives, and estrogen replace-
ment therapy for the control of menopausal symptoms.4
The
common denominator in all these risk factors is the length and
cumulative exposure to endogenous or exogenous estrogens.
More and more young women across the world are waiting
longer than ever to have their first child.7,8
Cultural factors,
socioeconomic conditions, and education levels play a role in
the decision-making about when to have a first child.7,8
The
current mean age of first-time moms is 26 years in the United
States, which is about a 5-year increase compared to 50 years
ago.7,8
Moreover, the number of first-time moms who are older
than 35 years is growing.8
These trends are likely to continue
and can be expected to increase BC incidence when women
reach menopausal years.
Giving birth to a first child before 24 years of age decreases
the BC risk by about half, when women reach menopausal
years.9-22
Each subsequent pregnancies and breastfeeding can
increase this protection. Pregnancies with a higher human chor-
ionic gonadotropin (hCG) levels correlate with a corresponding
decrease in BC risk.23,24
The pregnancy benefits are seen
among women worldwide and they progressively decrease as
the maternal age increases at the first childbirth.9-22
Thus,
women who complete full-term pregnancy at about 30 years
of age will have the same risk as nulliparous women.9-22
Com-
pleting full-term pregnancy at 35 years of age or later increases
the BC risk by about 20% relative to nulliparous women.9-22
These age-dependent mechanisms behind a progressive loss
and reversal of pregnancy benefits are not completely under-
stood. The risk does not increase or prognosis will not get
worse when women become pregnant after BC treatment.25,26
There are exceptions to the above epidemiological findings.
For example, some young women despite completing full-term
pregnancy can develop BC, especially during the first 5 years
after childbirth.9-22
Although the reasons are not known, there
are several possibilities. First and foremost is an absence of
optimal cellular differentiation in the breast, either due to hCG
levels not being quite high and/or the presence of biologically
inactive hCG variants. In either of these cases, pregnancy may
continue but the cellular differentiation may be suboptimal.
The second possibility is that these women may have genetic
alterations and/or activation of a group of genes that impede the
hCG actions.27,28
In support of this possibility are the findings
that hCG promotes mammary gland carcinogenesis in mice
bearing an activated erb-b2 receptor tyrosine kinase 2
(ERBB-2) oncogene.27
There could also be other reasons that
we do not know about yet. All these possibilities require further
interrogation through an additional research.
Studies on Rodent Mammary Tumor Model
The protective effect of first childbirth before the age of
24 years implies that it is likely conferred through hormones.
But the question is which hormone(s)? Pregnancy is a complex
physiological hormonal state, in which many hormones
change, some increase and others decrease. The changes are
hormone specific and each with a unique profile. Among these
hormones, hCG changes are considered a signature of human
pregnancy.29
For example, hCG starts increasing soon after
fertilization and appears in the circulation within few days.29
Subsequently, the levels exponentially increase during early
pregnancy, reaching a peak by about ninth week, followed by
a rapid decline to a low steady-state level (approximately 10%
of the peak) and remain there for the remainder of the preg-
nancy.29
This unique profile of hCG is primarily self-driven,
through a combination of positive and negative regulatory
mechanisms.29,30
The placenta also makes huge quantities of
estrogens and progesterone, and these levels, in contrast to
hCG, gradually increase and reach peaks during the second
half of pregnancy.29
To determine whether hCG could be behind the pregnancy-
induced protection against BC, Russo and Russo have pio-
neered in using chemically induced rat mammary gland tumor
model. In this model, a single intragastric instillation of 8 mg of
7, 12-dimethylbenz[a]anthracene (DMBA) results in the for-
mation of multiple mammary gland tumors in 100% of the
animals.31,32
This ability of DMBA was greatly reduced in
parous than in virgin animals.33,34
However, the virgin animals
can be made DMBA resistant by intraperitoneal injection of
hCG for 21 days, the length of rodent pregnancy.35-39
The hCG
administration is effective regardless of whether it is given
before, after, or simultaneously with DMBA, suggesting that
hCG can inhibit not only the initiation but also the progression
of carcinogenesis.35-39
Moreover, the hCG effects are dose
dependent, mimic pregnancy in breast cell differentiation, and
long-lasting as pregnancy itself.40,41
2 Reproductive Sciences

Since these experiments were performed in intact animals, it
is possible that the protective effect of hCG could have come
from the stimulation of ovaries to secrete estradiol and proges-
terone.42
Since estrogens are mitogenic,43-47
their participation
in BC protection is counterintuitive. Contrary to this expecta-
tion, Guzman et al have reported that a weeklong exposure to
pregnancy levels of estradiol and progesterone resulted in an
inhibition of chemically induced mammary gland carcinogen-
esis and this inhibition was attributed primarily to estradiol.48
If
luteinizing hormone (LH) levels were elevated, which have not
been measured in this study, then it could have played this
protective role, as rat mammary glands contain its receptors.49
The role of progesterone in the carcinogen-induced rat mam-
mary gland tumor model is unclear because of its paradoxical
effects, that is, low levels inhibit and high levels promote car-
cinogenesis.43
Moreover, the proliferation of breast epithelial
cells is the highest during mid-luteal phase, when progesterone
levels are at their peak.50
Paradoxically, high doses of estro-
gens and progesterone have been reported to induce cellular
differentiation in the breast.43
Whether it is the reason behind
the findings of Guzman et al has not been investigated. Gen-
erally, there has not been as much research on estrogens and
progesterone role in BC prevention as there is on hCG. There-
fore, further research is required to determine whether estradiol
and progesterone can be protective against BC as hCG.
The Mechanisms of the hCG Actions
in the Rodent Model
Pregnancy-induced protection against chemically induced
mammary gland carcinogenesis is seen among rats and mice.33
Since these animals do not have hCG, pregnancy benefits must
come from LH, the structural and functional homolog of hCG.
However, pregnancy profile of LH is not even remotely similar
to that of hCG in women. Thus, it is not clear how LH can
provide the same protection as hCG does, despite the lack of its
dramatic changes during rat and mice pregnancy.
The findings that support hCG is the most likely candidate
in the pregnancy-induced protection against BC in women, as
determined in a rodent model, raise a question of how does
hCG accomplish the task? The research of Russo and Russo
and others has provided some plausible answers.
Rodent mammary glands contain 4 types of lobules.41
Type
1 lobules, which are the most undifferentiated, primarily con-
tain terminal end buds. Type 2 lobules, which are differentiated
from type 1, have complex morphology and contain fewer
alveolar buds and a greater number of ductal structures per
lobule. The cells in both these lobules are highly proliferative,
have an increased DNA labeling index, and quite susceptible to
carcinogens.41
Type 3 and 4 lobules, which represent the
advanced stages of differentiation, are found during pregnancy
or after hCG treatment.41
In fact, recombinant and urinary
hCGs are equally effective as pregnancy in the induc-
tion.40,51-53
The epithelial cells of both type 3 and 4 lobules
are not proliferative and least susceptible to carcinogenic
changes.40,51-53
Virgin rats contain more type 1, few type 2, and no type 3
and 4 lobules.40,51-53
Pregnancy or hCG treatment induces the
differentiation of type 1 and 2 lobules into type 3 and 4
lobules.40
Both are not permanent structures, therefore, they
can regress into type 2 and then to type 1 lobules with
age.40,51-53
The hCG has multiple anti-BC actions in epithelial cells.54-68
They include increases in some and decreases in others. The
increases are the differentiation of cells, increased levels
of b-casein, perlecan, cytokeratin (CK)-18, E-cadherin,
connexin-26, apoptosis, insulin-like growth factor 1 binding
protein (IGFBP), inhibin, and DNA repair mechanisms. The
decreases are cell proliferation, PCNA, Ki-67, insulin-like
growth factor 1 (IGF1), and cell invasion. While some of the
changes can be correlated with an increase in cell differentia-
tion (b-casein, perlecan, CK-18, E-cadherin, connexin-26,
inhibin), others can be related to a decrease in cell proliferation
(IGF and IGFBP). The hierarchy among these multiple changes
in the same end response is unknown. Although the cellular
differentiation is important, it may not be sufficient to explain
the protective effects of hCG. For example, differentiation-
induced human placental lactogen (hPL) does not provide the
protection.31,32,41
Therefore, hCG must induce other changes
that hPL cannot. The hCG-induced changes include an induction
of permanent signature genomic imprinting, methylation, and
expression changes, whose molecular details have not been com-
pletely investigated.28,68-78
Human Studies on the Anti-BC Actions
of hCG
Since it is not possible to perform the kind of rodent studies on
women, investigators have turned to using BC cell lines, sur-
gical BC specimens, core needle breast biopsies, and BC xeno-
grafts grown in immunodeficient nude mice. These efforts have
led to an affirmation that hCG indeed protects against BC. For
example:
– The hCG treatment decreases the proliferation and inva-
sion of BC cells.57,79-81
The invasion response is more
pronounced than the proliferation.79
Both are time and
dose dependent, hormone specific, and require the pres-
ence of receptors.79
The hCG treatment also resulted in a
decrease in estrogen receptor levels, but they are not
related to the hCG actions on cell proliferation and
invasion.79
– The hCG treatment also reduces the survival of BC cells
after about 6 days of treatment.81
– Intramural injections of recombinant hCG into BC xeno-
grafts in immunodeficient nude mice resulted in an
increase in apoptotic index and a complete necrosis after
about 6 days of treatment.81
The apoptotic response was
specific as it was not observed in the ovaries.62
These
findings suggested that preoperative apoptosis induction
by hCG can be an effective neoadjuvant therapy for the
local control of the disease.81
Rao 3

– The patients with hCG/LH receptor-positive tumors
have a better prognosis during 5- to 12-year follow-up
period.82
– As rodents, human breasts also contain 4 types of
lobules.41
While nulliparous women primarily contain
type 1 lobules, parous women contain type 3 and 4
lobules, which represent maximal state of differentia-
tion.41
The postlactational involution results in the
regression of type 4 lobules into type 3 lobules, which
remain unchanged until about the fourth decade of life.41
By about the fifth decade, type 3 lobules regress into
type 1 lobules.41
As a result, postmenopausal parous
women only contain type 1 lobules, just like postmeno-
pausal nulliparous women. The difference is that cells in
type 1 lobules of postmenopausal parous women are not
proliferative and least responsive to carcinogenic stimu-
lus as compared with postmenopausal nulliparous
women.41
Obviously, previous pregnancies must have
endowed these cells with a protection from permanent
genomic imprinting and epigenetic changes.28,68-78
– Analyses of core needle breast biopsies from ethnically
homogeneous 71 parous and 42 nulliparous women
revealed a differential gene expression.76
It included
an upregulation of 267 genes and a downregulation of
38 genes in parous as compared with nulliparous
women.76
The upregulated genes included those
involved in cell differentiation and development,
anchoring of epithelial cells to the basement membrane,
hemidesmosomes, cell substrate assembly, and messen-
ger RNA (mRNA) and RNA processing and splicing.76
The downregulated genes prominently included those
involved in cell proliferation, that is, IGF receptor sig-
naling and so on.76
Paradigm Shift on the hCG/LH Actions
The hCG and LH are structural and functional homologs that
belong to glycoprotein hormone and cystine knot growth factor
families.83,84
The glycoprotein hormone family also includes
follicle-stimulating and thyroid-stimulating hormones. The
members of this family are heterodimers of noncovalently
bound a and b subunits. While the a subunits are common, the
b subunits are different, except hCG and LH.83
The b subunits
of hCG and LH are similar but not identical.83
The cystine
knot growth factor superfamily includes platelet-derived
growth factor, fibroblast growth factor b, nerve growth factor,
and transforming growth factor b2.84
These family affiliations
have implications for understanding the pleiotropic actions of
hCG/LH.
While human trophoblasts synthesize hCG, gonadotropes of
the anterior pituitary gland make LH.29,83
The hCG can also be
ectopically synthesized by a variety of other normal and cancer
cells.29
Ectopic hCG does not survive long enough in the cir-
culation to serve as an endocrine regulator. Instead, it primarily
serves as an autocrine and paracrine regulator, which will be
important for cancer biology. The presence of hCG and its
subunits in human BC cells and tumors has been
described.85-90
The expressions of genes in hCG b-encoding
gene cluster are not the same between BCs and normal tropho-
blasts.89
Since neither the subunits nor the hCG variants have
not been fully characterized, one cannot eliminate the possibil-
ity that the ectopic expression in BCs merely represents a reca-
pitulation of embryonic antigens.23
The hCG and LH bind to a common cell surface G protein-
coupled receptors.91,92
The receptors bind hCG with a higher
affinity than LH.93
Contrary to an initial belief, a recent study
showed that the receptors could differentiate recombinant hCG
from recombinant LH.94
For example, hCG was 5-fold more
active than LH in stimulating the cyclic adenosine monopho-
sphate (AMP) (cAMP) formation, hLH is more effective in
activating phospho–extracellular signal-regulated kinase
(ERK) 1/2 and protein kinase B (PKB), and the 2 hormones
do not necessarily activate the same genes or to the same
degree.94
These findings will have huge implications not only
for the anti-BC actions but also for all the other actions of these
2 hormones in various tissues.
As the name implied, investigators have believed for a long
time that hCG and LH are only capable of regulating gonadal
secretion of steroid hormones.95
The secreted steroid hormones
will then regulate the other tissues. This paradigm has begun to
shift as more and more investigators have found the presence of
hCG/LH receptors in many nongonadal tissues in the body.95
Human skin is one of them.96,97
Since mammary glands are
specialized accessory structures of skin, which are evolved to
provide nourishment to the offspring, a question arose whether
they also contain the receptors. The results revealed that they in
fact do.49
Nonpregnant, pregnant, lactating, and nonlactating
mammary glands contained the receptors with the higher levels
in epithelial cells, which secrete milk proteins, and the frequent
sites of the ductal origin of carcinomas. So far, mammary
glands of rat, sow, and human have been shown to contain the
receptors.49,79-82,98,99
The human data were obtained on normal
breast tissue, BC specimens, and commonly used BC cell lines
for research.79-82,98,99
Except for 1 report,100
all the others have reported that BC
specimens and cells contain varying receptor levels, which
should be expected considering the histopathological diversity
of BCs and how they are obtained and processed, that is, frozen
versus fixed, time delays, and so on.79-82,98,99
Among the cell
lines, MCF-7 cells contain higher receptor levels than
MD-MBA-231 and HBL-100 cells.79
The higher receptor
levels in MCF-7 cells are due to an increased receptor gene
transcription owing to a higher transcription factor, activator
protein-2 (Ap2) and Egr, levels.101
The receptor levels corre-
late with the cell responses.79
The responses, which are also
supported by biochemical changes, include decreased cell pro-
liferation and invasion across Matrigel-coated membranes.79
The responses are time and dose dependent, hormone specific,
cAMP/PKA mediated, and require the presence of receptors.79
In 5 different BC cell lines, hCG was able to decrease their
survival, which correlated with an expression and an activation
of hCG/LH receptors.82

The hCG treatment of MCF-7 cells prevented an activation
of NF-kB and Ap1, induced by tumor necrosis factor, which
was paralleled by a decrease in phosphorylation and degrada-
tion of nuclear factor of kappa light polypeptide gene enhancer
in B-cells, a (IkB).80
These responses were dependent on ade-
nyl cyclase activation and cAMP increase. Moreover, dibutyryl
cAMP and 8-bromo-cAMP mimicked the hCG actions and
cAMP inhibitor blocked the actions of both cAMP and
hCG.79-81,102
As nuclear translocation is necessary for NF-kB
and Ap1 to regulate the gene transcription, the prevention of
their activation abrogates the gene expression changes neces-
sary for a decreased cell proliferation and invasion and
increased cell differentiation.
The hCG/LH receptors have been used in targeted ablation
of rodent mammary gland tumors or to kill human BC
cells.103,104
In both the cases, hCG was conjugated with
HECATE or doxorubicin for targeted delivery, which appar-
ently spared normal receptor-containing cells from the destruc-
tion.103,104
The mechanistic basis for this differential normal
and cancer cells responses is unknown.
The BC protective effects were not observed in transgenic
hCG/LH overexpression models.105,106
These results are pre-
dictable from the dodgy approach, as incessant ovarian stimu-
lation results in a huge sustained estradiol and progesterone
levels, which promote mammary gland carcinogenesis. At the
same time, the chronically elevated hCG/LH levels can erase
the protective actions through receptor downregulation in the
mammary glands.
Overview of the Likely Mechanisms
of hCG Actions in BC
From the published studies on the hCG effects in rodent BC
models, human BC cells, xenografts, and gene expression pro-
filing in core needle biopsies, it is possible to suggest how
hCG/LH might act in BCs. The actions fall into nongenomic
and genomic pathways. In both pathways, cell surface receptor
binding and the second messengers generation will be the first
steps. Several second messenger systems seem to be involved,
and primary among them is cAMP/PKA.79
Others are PKB,
PKC, ERK I/2, mitogen-activated protein kinase, Wnt/b cate-
nin, and so on.107-109
It is possible that these second messenger
systems extensively cross talk to empower hCG/LH to accom-
plish all their varied actions. The nongenomic actions are rapid
and precede the long-term genomic actions.
– The nongenomic actions include the changes in phos-
phorylation of various kinases, cyclins, metalloprotei-
nase and their inhibitors, structural and functional
proteins, key enzymes, transcription factors and their
nuclear translocation, and so on. The preexisting mole-
cules will be involved in these changes.
– The genomic actions include activation and repression
of many gene families that are involved in cell differ-
entiation, proliferation, invasion, apoptosis, survival,
and so on. The genetic alterations may include epige-
netic changes.
The molecular details of the nongenomic and genomic path-
ways are unknown for the most part. Therefore, a great deal of
further research is required to investigate them.
Similar and Contrasting Roles of hCG/LH
and Estrogens in the Breast
The hCG/LH and estrogens are likely to have similar roles
during pregnancy, when the growth, development, and differ-
entiation in breasts are maximal.47
This does not necessarily
mean that these 2 classes of hormones influence the same cel-
lular structures, events, or to the same degree. Since breast is a
complex organ with multiple cell types and structures, it is
likely that they regulate some events similarly and others dif-
ferently. Lending credibility to this possibility are findings that
estrogen/progesterone replacement therapy can only partially
reverse the mammary glands phenotype in homozygous LH
receptor knockout animals.110
Contrasting roles are anti-BC actions of hCG/LH and pro-
BC actions of estrogens. The hCG/LH actions include inhibi-
tion cell proliferation, invasion and survival and stimulation of
differentiation, apoptosis, necrosis, an increase in ductal length
and tertiary branching, and the ability to abrogate the estrogen
actions on transformation and solid tumor formation.47,54-67
Estrogens, on the other hand, are established mitogens in the
breast.43-47
They can increase ductal width, disrupt luminal
architecture, and promote solid tumor formation.47
However,
they do not cause the disease unless the estrogen exposure is
prolonged and cumulative, as it happens when women had an
early menarche, late menopause, nulliparous, and long-term
use of only estrogen-containing birth control pills or estrogen
replacement therapy for the control of menopausal symp-
toms.4,43-47
Conversely, hCG/LH can only serve as anti-BC
during early reproductive life when women complete full-
term pregnancy before 24 years of age.9-22
The premise behind ovariectomy as a BC therapy, that is, a
drastic decrease in estrogen levels, can very well be due to an
elevation of LH levels.111
Likewise, the reduced BC prevalence
in college athletes (anovulation) and in women who had an
early menopause due to either natural causes or ovariectomy
could be related to a premature elevation of LH levels.19
All the
similar and contrasting actions of hCG/LH and estrogens in the
above scenarios likely involve complex cellular, biochemical,
molecular, and genetic networks, which are largely unknown
and should be investigated in the future studies.
Need for Further Research
Because the type of BC research that has been performed in
rodent models cannot be done on women, only close approx-
imations are possible. An ex-in vivo study, the type performed
by Lopez et al, is such a case.81
In these studies, hCG/LH
receptor-positive BC cells and tissue fragments made from
Rao 5

patient’s tumors can be implanted into immunodeficient nude
mice. Once the tumors develop, mice can then be used for
answering the following questions.
– Are recombinant hCG and hLH equipotent in their anti-
BC actions, as determined by cell differentiation, prolif-
eration, invasion, and apoptosis, after adjusting for their
differences in the circulatory half-lives?
– How does hCG/LH antagonize estrogen actions on BC
growth, development, and invasion?
– Do hCG/LH work best alone or in combination with
anti-estrogens and the other chemotherapeutic drugs?
– How does intratumoral injections compare with the
other routes of hCG administration?
– How does the effectiveness of intratumoral delivery of
nanoparticles coated with hCG compare with the free
hormone?
– Whether pretreatment of nude mice with hCG/LH will
have an impact on their ability to accept and support the
growth and development of implants?
In all these cases, both the animals and the tumors can be
subjected to multiple cell, biochemical, and molecular, genetic,
and immunological analyses. The answers can potentially pro-
vide useful information that may even be useful for decision-
making on the treatment options.
How Can We Use hCG to Prevent
and/or Treat the Disease?
In an era of more and more young women across the world are
waiting longer than ever to have their first child, they need
some kind of protection, so that they don’t have to face the
prospects of increased chances of developing BC, when they
reach menopausal age. The hCG could be useful in the preven-
tion strategy.19,112
In order to develop this strategy, the follow-
ing questions must be answered first in a rodent model.
– What is the optimal hCG dose? The initial dose selection
can be based on the hCGs use in the infertility treatments
in women, that is, 3000 to 10 000 IU.
– What is the minimal treatment length? Even though
pregnancy is 9 months long, the treatment may not have
to be that long. A shorter duration with high hCG doses
may do the job.
– What is the most effective mode of hCG delivery
between subcutaneous, intramuscular, intravenous, sub-
cutaneous, intraperitoneal, or sublingual as often used in
hCG weight loss clinics?
– Whether nanoparticle delivery of hCG delivery could be
more effective than the free hormone?
Once the answers are obtained, multinational randomized
placebo-controlled phase 1 clinical trials can be planned by
recruiting women volunteers of 24 years of age or younger who
are planning to delay their first childbirth. Women who already
have BC or certain oncogene activations should be excluded, as
there is evidence that hCG could promote their growth in some
oncogene activations.27
It is a daunting task to conduct phase 1 clinical trials and
then wait for several years to find out whether hCG treatment
worked. But there are no current alternatives to offer to the
young women who have decided to delay their first childbirth.
Given the weight of the evidence, hCG administration may
likely help this population. The other benefits to consider are
the low cost and minimal side effects, if any, with hCG. Any
minor inconveniences that women may face from the hCG
administration are rather a small price to pay for potential life-
time gain of benefits.
Another therapeutic context is the treatment of primary and
locally spread BCs. Since all the tumors will not be hCG
responsive, the presence of hCG/LH receptor must be estab-
lished first in core needle biopsies. Only when they contain the
receptors, then hCG can be injected into the tumors to induce
apoptosis/necrosis prior to surgical removal, as Lopez et al
have demonstrated in xenografts.81
The lower incidence of BC has been reported in women who
have taken hCG for weight loss.113
This assertion should be
further verified in age-stratified women who are going through
hCG weight loss clinics around the country. It is ill advised to
use hCG in known or suspected cases of certain oncogene
activations such as ERBB-2. However, it may be wise to
explore whether hCG can be useful in BRAC mutations in
improving the disease outcome, as breast epithelial cell differ-
entiation induced by hCG can diminish the same cellular
targets that the mutations might involve.
Finally, hCG for the prevention/treatment of BC may not
work for everyone, as no strategy does. It is a lot of work,
expense, and time to conduct the clinical trials. But we owe
this to an increasing population of young women in our soci-
eties, who are waiting longer than ever to have their first child.
In addition, there are reasons for optimism for the treatment
application of hCG, from the findings presented in this article.
So it is time to move forward testing hCG for the prevention
and treatment of BC.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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