1. Letter to the Editor
Can the risk of breast cancers be reduced in this
era of delayed first childbirths by treatment with
human chorionic gonadotropin?
Breast cancers are the most common malignancies among
women worldwide.1
The incidence increases with age, but the
disease in older women is less aggressive than in younger women.1
It is estimated that there will be about 246,000 new cases and
40,450 will die from the disease during 2016. However, deaths from
breast cancers are decreasing due to an early detection, discontin-
uation of the use of only estrogen containing oral contraceptive pills
and estrogen replacement therapy for the control of menopausal
symptoms and choosing healthy life styles.1
Currently, there are
about 2.8 million breast cancer survivors in the U.S. alone.1
There are no broad-brush strokes to predict who might or might
not develop breast cancer, because having risk factors does not
necessarily mean that the person will get the disease. Conversely,
there is no guarantee that women will not develop the disease even
though they do not seem to have any risk factors.1
The risk factors
fall into non-reproductive and reproductive categories.1
Non-
reproductive risk factors are, age, individual’s and family history of
the disease, radiation therapy of breast and chest, post-meno-
pausal obesity and mutations in tumor suppressor genes such as,
BRAC1, BRAC2 and others.1
About 5–10% of the breast cancer cases
are due to heredity.1
The reproductive risk factors include, early menarche, late
menopause, never have given birth to a child (nulliparous) or
giving first childbirth at about 35 years of age or after, long-term
use of use of only estrogen containing oral contraceptive pills and
estrogen replacement therapy.1
The common denominator among
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.2,3
Cultural factors, socio-
economic conditions and a level of education play an important role
in the decision making to postpone the first childbirth.3
The current
mean age of first time moms is 26 years in U.S., which is about a 5-
year increase compared with 50 years ago.3
Moreover, the number
of first time moms who are older than 35 years is growing.3
These
trends are likely to continue and can be expected to influence the
breast cancer risk when women reach menopausal years.
Giving birth to a first child before 24 years age decreases the
breast cancer risk by about half, when women reach menopausal
years.4–7
Multi-parity, multiple pregnancies (twin or greater) and
breast-feeding can also decrease the risk.4–7
The pregnancy
benefits are seen among women worldwide and they progressively
decrease as the maternal age increases at the first childbirth.4–7
Thus, women who complete full term pregnancy at about 30 years
of age will have the same risk as nulliparous women and those that
delay until 35 years of age or older have an increased risk
compared with nulliparous women.4–7
The mechanisms behind
this age dependent progressive loss and reversal of pregnancy
benefits are not known.
Russo and Russo et al. have provided an extensive evidence in
support of human chorionic gonadotropin (hCG) playing a
protective role against breast cancers.8
The work of others has
reaffirmed their findings. They include the presence of hCG/
luteinizing hormone (LH) receptors in human breast cancer cells
and tissues and their activation resulting in an increase in cell
differentiation and apoptosis and a decrease in cell proliferation,
invasion and survival.9–20
The hCG/LH receptors are required for
these hCG actions.15
Further support of these actions are the
findings that women with the receptor positive tumors tend to
have a longer metastasis free survival.21
Pregnancy and hCG treatment are equally effective in reducing
the breast cancer risk.8
Both of them induce permanent signature
genomic imprinting and expression changes that are characterized
by low cell proliferation, increased cell differentiation which make
the cells resistant to carcinogenesis, increased efficiency of DNA
repair mechanisms among others.22–27
These changes may explain
how decades after first pregnancy/hCG treatment can result in the
reduced breast cancer risk during menopausal years.
These findings could provide clinical opportunities for hCG use
in the risk reduction of breast cancers in this modern era of
increasing number of women delaying their first child birth into
their late 20 or 30 years of age. Since the delayed first childbirth
increases the breast cancer risk, these women would benefit from
some kind of protection, so that they do not have to face the
prospects of increased chances of developing the breast cancer,
when they reach menopausal age. hCG could be useful in the
prevention strategy. In order to develop the strategy, we must
answer the following questions.
- What is the optimal hCG dose to use?
- What is the minimal hCG treatment length to get the maximal
benefits?
- What is the most effective mode of hCG delivery between
subcutaneous, intramuscular, intraperitoneal, intravenous or
sublingual, as often used in hCG weight loss clinics?
- Whether nanoparticle delivery could make hCG therapy more
effective?
We may be able obtain preliminary answers to these questions
in a rodent model. Once they 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 breast cancer or certain oncogene activating
mutations should be excluded from the trials, as there is evidence
that hCG could promote breast cancer growth.28
It is a daunting task to conduct phase 1 clinical trials and then
wait for several years to find out whether hCG treatment worked.
Journal of Reproductive Health and Medicine xxx (2016) xxx–xxx
G Model
JRHM-36; No. of Pages 2
Please cite this article in press as: Rao CV. Can the risk of breast cancers be reduced in this era of delayed first childbirths by treatment
with human chorionic gonadotropin?, J Reprod Health Med. (2016), http://dx.doi.org/10.1016/j.jrhm.2016.08.001
Contents lists available at ScienceDirect
Journal of Reproductive Health and Medicine
journal homepage: www.elsevier.com/locate/jrhm
http://dx.doi.org/10.1016/j.jrhm.2016.08.001
2214-420X/ß 2016 Elsevier, a division of Reed Elsevier India, Pvt. Ltd. All rights reserved.

2. But there are no other choices to offer to young women, who have
decided to delay their first childbirth. Given the weight of the
evidence, hCG administration may likely reduce the risk of breast
cancers in this population. Other benefits to consider are the low
cost and minimal to no adverse side effects with hCG. Any minor
inconveniences that women may have to face from the hCG
administration are a small price to pay for potential life time gain of
benefits.
Finally, reducing the breast cancers risk by pharmacologic
mimicking of pregnancy may not work for every woman, as no
strategy does. It is a lot of work, expense and time to conduct these
clinical trials. But we owe this to an increasing population of young
women in our societies, who are waiting longer than ever to have
their first child.
References
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C.V. Raoa,b,
*
a
Department of Cellular Biology and Pharmacology, Herbert Wertheim
College of Medicine, Florida International University, Miami,
FL 33199, USA
b
Department of Molecular and Human Genetics and Obstetrics and
Gynecology, Reproduction and Development Program, Herbert
Wertheim College of Medicine, Florida International University,
Miami, FL 33199, USA
*Correspondence to: Department of Molecular and Human
Genetics and Obstetrics and Gynecology, Reproduction and
Development Program, Herbert Wertheim College of Medicine,
Florida International University, Miami, FL 33199, USA
E-mail address: crao@fiu.edu (C.V. Rao).
Received 13 July 2016
Letter to the Editor / Journal of Reproductive Health and Medicine xxx (2016) xxx–xxx2
G Model
JRHM-36; No. of Pages 2
Please cite this article in press as: Rao CV. Can the risk of breast cancers be reduced in this era of delayed first childbirths by treatment
with human chorionic gonadotropin?, J Reprod Health Med. (2016), http://dx.doi.org/10.1016/j.jrhm.2016.08.001