1) The document discusses the potential of using human chorionic gonadotropin (hCG) as a therapy for rheumatoid arthritis (RA) and Sjögren's syndrome (SS). HCG contributes to immune tolerance during pregnancy, which alleviates symptoms of these autoimmune diseases. 2) Animal studies show that hCG treatment mimics the benefits of pregnancy for RA and SS, reducing inflammation and immune responses. 3) HCG's immunosuppressive and anti-inflammatory properties suggest it could provide an alternative to current RA and SS therapies, with fewer side effects. Randomized clinical trials of hCG are recommended.

1. Review
Potential Therapy for Rheumatoid Arthritis
and Sjo¨gren Syndrome With Human
Chorionic Gonadotropin
C. V. Rao, PhD1
Abstract
Autoimmune diseases such as rheumatoid arthritis (RA) and Sjo¨gren syndrome (SS) ameliorate during pregnancy, through
dampening (immunotolerance) of the maternal immune system which protects the fetus from rejection. A large number of studies
have shown that human chorionic gonadotropin (hCG) contributes to this tolerance. Studies on animal models have reaffirmed
that hCG treatment mimics the benefits of pregnancy. Based on the scientific evidence, randomized clinical trials comparing hCG
with current therapies and/or placebo are recommended for RA, SS, and for other autoimmune diseases such as, type 1 diabetes
and ankylosing spondylitis, which also get better during pregnancy and hCG treatment seems to help.
Keywords
human chorionic gonadotropin, rheumatoid arthritis, Sjo¨gren syndrome, autoimmune diseases, pregnancy, fetal rejection,
immunotolerance, cells of the immune system
Introduction
Rheumatoid arthritis (RA) is an autoimmune disease in which
body’s immune system mistakenly attacks joints, instead of
attacking bacteria and viruses.1,2
Small and large joints of
hands and feet are usually affected.1,2
They become inflamed,
swollen, stiff, reducing the mobility and quality of life. Comor-
bidities include cardiovascular disease, infections, mental
health conditions, and malignancies.3
According to the US
Center for Disease Control and Prevention and Arthritis Foun-
dation, about 1.5 million people have the disease and the num-
ber of new cases appear to be increasing.4,5
Early diagnosis and
treatment are key to the prevention of further bone, cartilage,
and other organ damage. Left untreated, RA can lead to perma-
nent joints damage, disability, and even death due to involve-
ment of other organ systems.6
Sjo¨gren syndrome (SS) is also an autoimmune disease in
which multiple exocrine glands, such as lacrimal and salivary
glands, which provide tears and saliva, are affected.7
As a
result, their secretions markedly decrease, resulting in distres-
sing dryness of eyes and mouth. Respiratory tract and vagina
can also become dry. The risk of developing lymphoma
increases by about 40-fold, and peripheral and central nervous
system can also get involved. According to 2014 Arthritis
Foundation report, approximately 4 million Americans have
this disease, which makes it the most prevalent autoimmune
disease.
The combined numbers of RA and SS will be much higher
worldwide. There is no known single cause, but prevailing
theories suggest that a combination of genetic and environmen-
tal factors play a role in triggering the immune system into
overdrive.1,2
High human and economic costs are associated
with these diseases.8-10
Human cost includes, chronic pain and
suffering, too sick to work, which results in job loss and health
insurance. The economic cost is the long-term use of immuno-
suppressive and anti-inflammatory drugs, some of which can
be quite expensive. The prevalence of both these diseases is
higher among women than in men.11
Both RA and SS fre-
quently occur together (Sjo¨rgren Syndrome Foundation). The
current therapies use immunosuppressive synthetic glucocorti-
coids, nonsteroidal anti-inflammatory agents, and nonbiologic
disease-modifying antirheumatoid arthritis drugs (DMARDs)
to relieve the symptoms, slow the disease progression, and
reduce further tissue damage. Some of these drugs have devas-
tating side effects. Thus, there is a clear need for anything that
might reduce treatment costs and the toxicity of the drugs.
1
Department of Cellular Biology and Pharmacology, Molecular and Human
Genetics and Obstetrics and Gynecology, Reproduction and Development
Program, Herbert Wertheim College of Medicine, Florida International Uni-
versity, Miami, FL, USA
Corresponding Author:
C. V. Rao, Department 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
2016, Vol. 23(5) 566-571
ª The Author(s) 2015
Reprints and permission:
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DOI: 10.1177/1933719115597765
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2. Paradigm Shift on the Human Chorionic
Gonadotropin Actions
Human chorionic gonadotropin (hCG) is a hallmark hormone
of pregnancy. It has a typical pregnancy profile, in which the
levels exponentially increase during early pregnancy, reaching
a peak by about ninth week, followed by a rapid decline to a
lower steady levels and remain there until the end of preg-
nancy.12
Self-regulation of hCG biosynthesis, involving both
positive- and negative-feedback mechanisms, could explain
this profile.13-16
While profiles remain relatively constant, the
absolute hCG levels could vary a great deal among individuals
and in different pregnancies of the same individual.12
Until about 1990, hCG was only considered to rescue corpus
luteum from regression in a fertile cycle and maintain its pro-
gesterone secretion, until placental shift of its synthesis is com-
pleted by about the ninth week.12
Thereafter, hCG was
considered a vestigial hormone. This textbook description of
hCG had begun to change with published data from around the
world, which showed that functional hCG receptors, which also
bind its structural and functional homolog, luteinizing hormone
(LH), are also present in many maternal and fetoplacental
tissues.17-20
Some of these tissues include, reproductive tract,
placenta, fetal membranes, decidua, several fetal tissues,
vasculature, and the cells of the immune system, such as regu-
latory T cell (Tregs), monocytes, macrophages, and dendritic
cells.17-24
Although much remains to be investigated, it is
becoming increasingly clear that hCG is a pleiotropic hormone,
whose actions are likely to be important for an initiation and
maintenance of pregnancy.17-20,25
At the end, it also seems to
have a permissive role in normal labor progression.25-29
The
initiation and maintenance of pregnancy likely involve many
hCG-driven changes in maternal and fetoplacental tissues. One
of them is the prevention of fetal rejection by the maternal
immune system.30-39
This wealth of findings opened new pos-
sibilities of hCG use to increase the implantation and clinical
pregnancy rates of in vitro fertilization procedures and to treat
several pregnancy complications.17-19,40-54
Evidence Linking hCG to Potential Therapy
for RA and SS
The first clue came from the clinical observations that the
symptoms of RA and SS ameliorate during pregnancy.55-60
The
RA flares up during the postpartum period, especially after
the first pregnancy, which was thought to be due to hormonal
changes and/or to the exposure to paternal HLA antigens.61
Theoretically, the benefits can accrue from any of the preg-
nancy hormones. Some of them increase, while others decrease
and the onset of changes vary with the hormone.12
The evi-
dence pointing to hCG came from the findings that it has
immunosuppressive and anti-inflammatory properties, which
current therapies target.62
Two animal models have been used
to test the effectiveness of hCG.
The first model was streptococcal cell wall (SCW)-induced
arthritis in nonpregnant rats.63
When SCW was injected, the
animals develop the signs and symptoms of RA within 2 days,
which resemble human disease. These include, swelling,
erythemia, and distortion of wrist and ankle joints; infiltration
of proinflammatory cells into the joints, bone, and cartilage
destruction; and the increased production of tumor necrosis
factor (TNF) a, interleukin (IL)-6, IL-1b, nitric oxide (NO),
and inducible nitric oxide synthase (iNOS). Injection of either
clinical grade or recombinant hCG, 2 days before the SCW
injection, resulted in a dose-dependent decrease in the develop-
ment of arthritis, blocked pathogenic changes typically associ-
ated with chronic disease phase, amelioration of symptoms,
decreased infiltration of proinflammatory cells, cytokines,
NO, and iNOS levels, bone, and cartilage destruction. While
the dimer hCG had dramatic suppressive effects, the isolated
a and b subunits had minimal effects, unless their doses are
increased by about 4-fold.
Nonobese diabetic (NOD) mice are common models for
autoimmune diseases research, including SS.64
These mice
show a decreased salivary flow, invasion of CD4þT, and B
lymphocytes into their salivary glands by 12 to 24 weeks of
age. These changes are very similar to those seen in salivary
glands of patients with SS. The hCG treatment from 6 to 12
weeks age resulted in a marked increase in salivary secretion
and a significant decrease in lymphocytes infiltration, damage to
salivary gland parenchymal cells, and a decrease in interferon g,
TNF-a, IL-1b, IL-10, iNOS, and matrixmetalloproteinase-9
levels.64
Scientific Basis of Therapeutic Benefit of hCG
Pregnancy is an immunotolerant state in which fetus is pro-
tected from an attack by the maternal immune system. A large
number of studies have now shown that hCG contributes to this
tolerance.30-39
Although, many knowledge gaps remain in the
complete understanding of how hCG works, it is widely recog-
nized that the same mechanisms are likely at work in protecting
the fetus as well as in providing the benefit against of RA and
SS. The published studies have shown that hCG uses the fol-
lowing mechanisms.
1. Pregnancy is a type 2 T helper (humoral immunity)
dominated state, which is induced by hCG from type
1 T helper (cell-mediated immunity) state.62
2. Increasing hCG levels coincide with the development of
immunotolerance at the local tissue and systemic lev-
els.15
At the local level, hCG increases the number of
uterine natural killer cells and induces the apoptosis
of T cells in decidua through Fas/Fas-ligand system.65
In addition, hCG promotes the function of macrophages
to clear apoptotic cells and to resolve the inflammation
and act to upregulate endometrial C3 and C4A/B gene
expression to modulate decidual immunity66,67
3. The hCG also upregulates at local level indoleamine
2,3-dioxygenase in syncytiotrophoblasts and in dendritic
cells which degrades tryptophan.68,69
This degradation
removes the proliferative stimulus for the effector cells
Rao 567
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3. at maternal–fetal interface and also their activation. As a
result, these cells cannot attack fetal tissues, thus sparing
the fetus from rejection.70
Further corroborating evi-
dence showed that coculture of syncytiotrophoblasts
with allogeneic lymphocytes induces an apoptosis in T
cells, and hCG treatment enhances this process.68-71
4. At systemic level, hCG treatment increases levels of
IL-10 and anti-inflammatory cytokine IL-27 and reduces
proinflammatory cytokine IL-17.72
5. Systemic immunotolerance also involves the expansion
and migration of Tregs to maternal–fetal interface by
hCG.72,73
6. In addition, hCG also induces the expansion of regula-
tory B cells. The expansion increases IL-10 secretion
and decreases TNF-a production by T cells74,75
7. Treatment with hCG enhances the mobilization of tol-
erogenic dendritic cells, induces the upregulation of
MHC class II antigens and IL-10 secretion, while keep-
ing nontolerogenic dendritic cells immature, tissue
bound, and promoted to undergo apoptosis.24,69,76
8. hCG injections can delay the rejection of allogeneic
skin grafts.72
The above-mentioned mechanisms are likely to be highly
integrated and coordinated in order to shelter the fetus from the
rejection and mother and fetus against the infections. While the
local and systemic mechanisms are important for pregnancy
continuation, the latter is likely to provide the benefit against
RA and SS.
Potential hCG Use for Other Autoimmune
Diseases
There are nearly 80 to 100 autoimmune diseases, with another 40
having some autoimmune basis. It is not likely that hCG will be
effective against all of them. In fact, pregnancy worsens the
symptoms of lupus erythematosus, an autoimmune disease,
which result from an increased antibody production by autoreac-
tive B cells.77,78
There are other autoimmune diseases, such as
type 1 diabetes, ankylosing spondylitis, multiple sclerosis, thyr-
oiditis, and Crohn disease, which also seems to improve during
pregnancy.60
Among them, hCG has been tested against ankylos-
ing spondylitis in men and type 1 diabetes in NOD mice.79-82
In both cases, hCG treatment has been found to be beneficial.
Why Does hCG Therapy Merit Consideration
The hCG, being a physiological hormone, has considerable
advantages over the currently used synthetic glucocorticoids,
nonsteroid anti-inflammatory drugs, and DMARDs. Some of
them can be quite expensive and come with severe side effects.
The hCG, by comparison, is not expensive and can be made
even cheaper by scaling up the production of recombinant hor-
mone. The hCG has minimal side effects and the commonly
described ones from the intramuscular injection are pain at the
injection site, abdominal bloating, abdominal and pelvic pain,
nausea, vomiting, and so forth, which do not often require med-
ical attention. If hCG is proven effective, there are many pos-
sibilities to improve upon how hCG can be administered. For
example, long-acting analogs and synthetic hCG mimetics for
oral use can be developed. Although, regular hCG cannot be
taken orally, due to its degradation in stomach, it can be taken
as lozenges, as hCG weight loss clinics promote. The active
ingredient, in a lozenge, would slowly dissolve and rapidly get
into buccal blood circulation. The hCG delivery by nanoparti-
cle is another potential area for development. The nanoparticle
delivery can reduce the dose and frequency of administration.
Based on the scientific data, randomized clinical trials can
be recommended. Potentially, there is much to gain from such
trials not only for RA and SS but also for other autoimmune
diseases such as type 1 diabetes and ankylosing spondylitis,
which also improve during pregnancy and hCG treatment
seems to help.79-82
It is possible that hCG may be effective not
only on its own but also work in combination with lower doses
of currently used drugs. Such combinations could be more
effective than single treatments, due to possible differences
in their modes of action. In addition, combination therapies can
save money and lowers the overall toxicity. As hCG is already
being used in reproductive medicine, it is possible to optimize
the treatment conditions with respect to the dose and treatment
frequency, rather quickly. In addition, the possibility of deli-
vering the lower doses of hCG directly into joint synovial fluids
of patients with RA can be explored. This route can reduce the
hCG dose and further minimize any side effects. The potential
hCG use for the treatment of RA and SS suggests that the hCG
administration for other clinical indications may change the
rate and progression of inflammatory/rheumatic diseases. This
possibility requires verification by further research. Until more
data become available, women with endometrial or ovarian
cancers or Alzheimer disease or with a strong family history
should be excluded from the hCG therapy because of the poten-
tial LH involvement in these diseases.83-89
Finally, as other
treatments, hCG therapy may not be a panacea, but it is likely
to become an important part of physicians tool box to treat
patients suffering with RA, SS, and few other autoimmune
diseases.
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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