Online Article

Original Article
Therapeutic Potential of Human Chorionic
Gonadotropin Against Painful Bladder
Syndrome/Interstitial Cystitis
C.V. Rao, PhD1
Abstract
Painful bladder syndrome/interstitial cystitis is a debilitating chronic bladder disease that primarily affects women. The disease is
due to a damage of urothelial cell lining. As a result, potassium particles and other toxic substances in urine can leak into bladder
mucosa, causing the symptoms of lower abdominal/pelvic discomfort, pain, increased urination frequency, urgency, nocturia, and
so on, all of which can substantially reduce the quality of daily life. There are multiple symptom reliving therapies. Among them,
only pentosan polysulfate sodium, sold under the brand name of Elmiron, has been approved for oral use by US Food and Drug
Administration. It provides the relief after several months of use. Based on the scientific leads presented in this article, we propose
that human chorionic gonadotropin has a therapeutic potential that is worth investigating for the treatment of this disease.
Keywords
hCG/LH receptors, urinary bladder, urothelial cells, painful bladder syndrome, interstitial cystitis, gonadotropins
Introduction
Painful bladder syndrome (PBS), also called interstitial cystitis
(IC), is a debilitating chronic urinary bladder disease.1-4
Even
though it is traditionally considered a women’s disease, men
also can get it.1-8
Women of all races, ethnic, and socioeco-
nomic backgrounds are susceptible.1,8
The disease can strike at
any age, but it is more prevalent among 40- to 60-year-old
women.1,8
The disease is characterized by lower abdominal/
pelvic pressure, discomfort, tenderness, or intense pain that
increases as the bladder gets full and empties.1-4,9-13
In addi-
tion, the patients suffer from frequent urination, urgency, noc-
turia, dyspareunia, and pain/discomfort while sitting, driving,
and traveling in a car.1-4,9-15
The symptoms vary with the per-
son and from time to time in the same person.12-15
In severe
cases, the intense pain can persist both day and night for more
than 2 years.9-15
Living with PBS/IC is extremely difficult because of pain
and suffering, staying home, social isolation, emotional trou-
bles, sexual intimacy problems, depression, and sleep depriva-
tion.1-4
According to some estimates, 7.9% of all women may
have early symptoms of PBS/IC.16
The economic burden of
this disease is very high and it exceeds that of many other
similar diseases.16,17
For example, total annual medical costs
per person can exceed US$ 7000, not including income loss
from missed work.
Due to the overlapping symptoms, PBS/IC diagnosis is
made by an exclusion of urinary tract infections and overactive
bladder.18-20
Urothelial cells are damaged in PBS/IC, which
was thought to be due to defective protective glycosaminogly-
can layer of bladder mucosa.21-25
The damaged cells do not get
replaced, because of antiproliferative factors that the damaged
cells seem to produce21-25
However, the nature of these factors
remains unknown. Potassium particles and other toxic sub-
stances in urine leak into damaged bladder mucosa, causing
inflammation and irritation.1-4
This can lead to scarring and
stiffening of bladder wall, which reduces the bladder capacity
to hold urine and can contribute to bladder pain during urine
accumulation and emptying.1-4
Many factors, such as bladder trauma from pelvic surgery,
bladder over distension, dysfunctional pelvic floor muscles,
autoimmunity, infections, primary neurogenic inflammation,
spinal cord trauma, and so on, are thought to be responsible
for PBS/IC.21-25
Multiple therapies exist, but they can only
provide a symptomatic relief.23-26
Moreover, they do not work
for everyone and the symptoms usually return after few
1
Departments of Cellular Biology and Pharmacology, Molecular and Human
Genetics and Obstetrics and Gynecology, Reproduction and Development
Program, Herbert Wertheim College of Medicine, Florida International
University, Miami, FL, USA
Corresponding Author:
C.V. Rao, Departments of Cellular Biology and Pharmacology, Molecular and
Human Genetics and Obstetrics and Gynecology, Reproduction and
Development Program, Herbert Wertheim College of Medicine, Florida
International University, Miami, FL 33199, USA.
Email: crao@fiu.edu
Reproductive Sciences
1-8
ª The Author(s) 2016
Reprints and permission:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/1933719116639139
rs.sagepub.com
at FLORIDA INTERNATIONAL UNIV on March 23, 2016rsx.sagepub.comDownloaded from

months.23-26
The therapies include IC diet, self-management,
physical therapy, oral medications (antidepressants, antihista-
mines, etc), nerve stimulation, bladder distension, bladder
instillations, immunosuppressants, and surgery.26-29
Elmiron,
the brand name for pentosan polysulfate sodium (PPS), is the
only US Food and Drug Administration (FDA) approved drug
for oral use.30
Most of the orally taken PPS is eliminated in the
feces due to lack of absorption.31
Pentosan polysulfate sodium
is also available for bladder instillations and they are effective
against pain, urgency, and frequency, but not nocturia.30,32
Although the mechanisms of PPS action are not known, it is
believed that it coats the urothelial cell lining of bladder, thus
protecting it from the harmful effects of toxic substances in the
urine.30,32
Pentosan polysulfate sodium is effective after sev-
eral months of use. Because, it is a weak blood thinner, its use
can increase the risk of bruising/bleeding from the nose and
gums.30,32
The other common side effects include diarrhea,
nausea, upset stomach, bloody stools, headache, hair loss, rash,
and dizziness.32
Botox (onabotulinumtoxinA) therapy is con-
sidered when the other bladder instillations have failed.33
But it
can also have serious side effects.34
Based on the scientific
leads, we propose that human chorionic gonadotropin (hCG)
has a therapeutic potential that merits consideration of its eva-
luation in the treatment of PBS/IC.
Evidence Linking hCG to the Potential
Therapy of PBS/IC
Uterus and urinary bladder are homologous organs because of
their common embryological origin, hollow nature, and over-
lapping cell and molecular networks.35-37
The shared gene net-
works include hCG/luteinizing hormone (LH) receptors and
parathyroid hormone-related protein genes.35,36,38-40
The latter
is a stretch-induced gene.35,36
Among these 2 genes, hCG/LH
receptor is relevant to PBS/IC, because of its overexpression in
urothelial cells, the sites of damage in PBS/IC, and hCG’s
potential to repair the damage.38
Human chorionic gonadotropin and LH are critical to
female and male reproductive competence.41
Both are hetero-
dimeric glycoprotein hormones.41
While hCG is secreted by
human placental syncytiotrophoblasts, LH is secreted by gona-
dotropes in the anterior pituitary gland.41
Human chorionic
gonadotropin is a human pregnancy hormone and it has a typ-
ical pregnancy profile.42
Thus, its levels exponentially increase
during early pregnancy, reaching a peak by about ninth week,
followed by a rapid decline to low steady state levels and
remain there until the end of pregnancy.42
Luteinizing hor-
mone, on the other hand, is present in all species and its levels
gradually increase until ovulation and then fall.42
In a fertile
cycle, LH levels decrease to low steady-state levels and remain
there until the end of pregnancy.42
Human chorionic gonadotro-
pin and LH are structural and functional homologs that belong to
cystine-knot growth factors superfamily, which includes platelet
derived growth factor, transforming growth factor b, and nerve
growth factor.43
Human chorionic gonadotropin and LH bind to
the same G-protein coupled cell surface receptors.41,44
Human
chorionic gonadotropin is more active than LH in vivo because
of its glycosylation, which prolongs the circulatory half-life, and
higher receptor-binding affinity.41,45
Multiple studies have revealed that functional hCG/LH
receptors are also present in many nongonadal tissues, includ-
ing, urinary bladders of women.38-40,46-52
The epithelial
(urothelium) cells contain higher receptor levels than detrusor
muscle and blood vessels.38
The urothelial cells from bladder
dome and trigone contain a similar receptor level.38
The
urothelial cells from younger and older women contain the
receptors, with higher levels in premenopausal than in postme-
nopausal bladders.38
The following observations suggested that hCG may have a
therapeutic value against PBS/IC.
1. The symptoms of PBS/IC seem to improve during
pregnancy and during infertility treatments with
hCG.40,53-56
2. Human chorionic gonadotropin has pleiotropic actions
in uterine epithelial cells,57-64
which are the homologs
of urothelial cells. This makes it possible for hCG to
also regulate urothelial cells. In fact, treatment of por-
cine urothelial cells with hCG results in an increase in
cyclic AMP levels and an upregulation of cyclooxygen-
ase (COX)-2, but not COX-1, gene expression.39
3. For hCG to regulate, urothelial cells must contain its
receptors, which they do.38-40
4. As a member of cystine-knot growth factors superfam-
ily, hCG can be expected to have pleiotropic effects in
cells that it targets.
5. Finally, some of the PBS/IC cases may have an auto-
immune etiology.22-24
The autoimmune diseases such
as rheumatoid arthritis and Sjo¨gren syndrome amelio-
rate during pregnancy and this improvement can be
mimicked by the hCG administration in the animal
models of these diseases.65-67
The Mechanisms of hCG Action That Can
Potentially Explain its Therapeutic Potential
Urothelial cell damage is a prerequisite to what happens in
PBC/IC. It is unknown what causes this damage. The ideal
therapeutic agent should either prevent the cell damage or
reverse the damage and/or replace the damaged cells. Human
chorionic gonadotropin may have this potential based on its
known actions in uterine and other cells.57-64,68-86
Thus, the
activation of urothelial cell hCG/LH receptors may result in
cell, molecular, and biochemical changes that may explain the
beneficial effects of hCG. The following mechanisms can be
envisioned from the hCG actions in the other cell systems.
a. Human chorionic gonadotropin binds to urothelial cell
surface receptors to activate them.
b. The activated receptors may stimulate, as in other cells,
primary signaling pathway, such as cyclic AMP, protein
kinase (PK) A, and secondary pathways, such as PKC,
2 Reproductive Sciences

mitogen-activated PK, and Wnt/b-catenin, and promote
their crosstalk.87-96
c. The second messengers can then activate/inhibit other
downstream kinases, protein phosphorylation/depho-
sphorylation, and score of other changes.
d. The other changes may include an increase in cell pro-
liferation and prevent further cellular damage.
e. The dampening effect of hCG on the immune system
could result in an inhibition of immune cells migration
and their ability to secrete cytokines in the vicinity of
urothelial cells.97-99
These changes together with anti-
inflammatory changes promoted by hCG, such as an
inhibition of NF-kß activation and nuclear transloca-
tion, may further reduce urothelial cell damage.100
f. As in human uterus,101,102
possible activation of bladder
vascular hCG/LH receptors may result in an increase in
blood flow. This increase may overall contribute to the
beneficial effects of hCG against PBC/IC.
Further hCG Research on Urothelial Cells
Similar to currently used drugs for the treatment of PBS/IC,
there is very little data on what hCG does in urothelial cells.
Studies are needed to investigate them not only in human
urothelial cells but also in animal models of PBS/IC. The fol-
lowing questions can be addressed.
a. Does hCG promote urothelial cells proliferation and
prevent their damage, and if so how?
b. Does hCG have immunosuppressive and anti-
inflammatory actions at the level of urothelial cells?
c. Does hCG regulate the urothelial cells secretion of cyto-
kines, chemokines, growth factors, and eicosanoids, and
what specific autocrine and paracrine roles do they play?
d. What nongenomic and genomic mechanisms does hCG
use in regulating urothelial cells?
e. How can the hCG actions be rationalized in term of its
therapeutic potential against PBS/IC?
f. Can hCG work in synergy with other therapeutic agents
such as PPS?
g. In addition to the above questions, it will be interesting
to determine whether elevated LH levels during preo-
vulatory period, postmenopause, or polycystic ovarian
disease can alter voiding changes.
The answers will greatly improve our current understanding
on the bladder actions of hCG and LH.
Pentosan Polysulfate Sodium Versus Human
Chorionic Gonadotropin
It is useful to compare the FDA approved PPS with hCG which
is yet to be tested against PBS/IC. Pentosan polysulfate sodium
is a semisynthetic 4000 to 6000 Da plant derived heparin like
molecule that is chemically and structurally similar to glyco-
saminoglycans.103,104
The mechanisms of its actions are
unknown. However, it is believed to work by coating the bladder
mucosa through an inhibition of mast cells migration, histamine
secretion, intracellular Ca2þ
levels, and so on.30-32,103-107
Human chorionic gonadotropin, on the other hand, is a
well-characterized heterodimeric glycoprotein hormone of
about 40 000 Da in size.41
It consists of dissimilar a and b
subunits.41
It has a complex carbohydrate structure, which
accounts for about 30% of its mass.41
Human chorionic gonado-
tropin has been extensively characterized with respects to its
structure and function, the regulation of transcription and trans-
lationofsubunitgenes,posttranslationalmodifications,secretion,
and so on.108-110
Human chorionic gonadotropin receptors have
been cloned, sequenced, and extensively characterized.111,112
Why Does hCG Therapy Merit
Consideration?
Among the wide range of current PBS/IC therapies, only the oral
PPS use has been FDA approved. But it has several tolerable side
effects. Human chorionic gonadotropin may also work for the
reasons previously indicated. It will have minor side effects, if
any, when administered by intramuscular (IM) injections. These
side effects do not often require medical attention.
The author suggests an evaluation of the therapeutic poten-
tial of hCG against PBS/IC. It can come from clinical trials
similar to those performed for PPS.113,114
Human chorionic
gonadotropin can be administered by an IM injection, or as
an oral medication in the form of lozenges, or as a bladder
instillations. It is also possible to develop stable hCG analogs,
mimetics, and nanoparticle delivery, and so on, which can
lower the dose and the frequency of treatment. Among these
treatment modalities, perhaps bladder hCG instillations will be
more interesting to explore because they will deliver the hor-
mone where it is most needed. In addition, any minor side
effects that are associated with IM injections become irrele-
vant. The other possible consequences of chronic hCG admin-
istration such as an interruption of cycles, abnormal bleeding
short-term infertility, and so on are a small price to pay in
exchange for the potential gain of treatment benefits against
this painful disease.
Dimethyl sulfoxide and PPS are administered by bladder
instillations either alone or in combination with local anes-
thetics.1-4,107
These instillations should be repeated to keep the
symptoms under control. In a trial setting, hCG instillations can
be compared with them. The combination instillations may
work better than single instillations, due to possible differences
in their mode of action. In addition, hCG inclusion can reduce
the toxicity, doses, and cost of other drugs. Human chorionic
gonadotropin may not replace other therapies but it can com-
plement them. Finding a cure for PBS/IC is a daunting task.
Any therapeutic agent or a combination of them that can pre-
vent cell damage, repair, or replace the damaged cells in
urothelial cell lining will provide a cure. It remains to be seen
whether an introduction of hCG in the therapeutic regimen can
improve the chances of coming close to accomplishing
this goal.
Rao 3

Human chorionic gonadotropin is already cheap and can be
made even more cost-effective by increasing the production of
recombinant hormone. Until more data become available, it is
prudent to withhold the hCG treatment from women who have
endometrial and ovarian cancers and Alzheimer disease or those
who have family history of them. This recommendation is based
on the reports that implied that LH may promote these dis-
eases.115-122
It is also worth considering the hCG therapy for
men, even though hCG/LH receptor presence in male urothelial
cells is not known.
As others, PBS/IC is a multifactorial disease. Consequently,
no single therapy works for every patient. Human chorionic
gonadotropin therapy, as the other existing ones for PBS/IC,
will be no exception. Thus, hCG therapy will not be a panacea,
but it has a potential to become an important item in urogyne-
cologists and urologists tool box to treat patients with PBS/IC.
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.
References
1. Nickel JC. Interstitical cystitis a chronic pelvic pain syndrome.
Med Clin North Am. 2004;88:467-481.
2. Swift SE, Chai TC, Bent AE. Painful conditions of the lower
urinary tract including painful bladder syndrome. In: Bent AE,
Cundift GW, Swift SE, eds. Ostergard’s Urogynecology and
Pelvic Floor Dysfunction, 6th ed., Chapter 8. Philadelphia,
PA: Lippincott Williams & Wilkins; 2008: 106-132.
3. Centers for Disease Control and Prevention. What is interstitial
cystitis (IC)? Web site. http://www.cdc.gov/ic/index.html. Pub-
lished January 2015. Updated February 9, 2016. Accesed July 1,
2015.
4. Interstitial Cystitis Association. What is interstitial cystitis (IC)?
Web site. http://www.ichelp.org/about-ic/what-is-interstitial-
cystitis/. Published January 9, 2015. Accesed July 1, 2015.
5. Koziol JA. Epidemiology of interstitial cystitis. Urol Clin North
Am. 1994;21(1):7-20.
6. Simon LJ, Landis R, Erickson DR, Nyberg LM; The ICB Study
Group. The interstitial cystitis data base study: concepts and
preliminary baseline descriptive statistics. Urology. 1997;
49(suppl 5A):64-75.
7. Interstitial Cystitis Association. Men & IC. Web site. http://
www.ichelp.org/about-ic/men-ic/. Published September 12,
2012. Accessed July 1, 2015.
8. Interstitial Cystitis Association. Women & IC. Web site. http://
www.ichelp.org/about-ic/women/. Published January 12, 2010.
Accessed July 1, 2015.
9. Parsons CL. Interstitial cystitis: clinical manifestations and diag-
nostic criteria in over 200 cases. Neurol Urodyn. 1990;9:
241-250.
10. Driscoll A, Teichman JMH. How do patients with interstitial
cystitis present? J Urol. 2001;166(6):2118-2120.
11. Persu C, Cauni V, Gutue S, Blaj I, Jinga V, Geavlete P. From
interstitial cystitis to chronic pelvic pain. J Med Life. 2010;3(2):
167-174.
12. Interstitial Cystitis Association. Symptoms of IC. http://www.
ichelp.org/about-ic/symptoms-of-ic/. Published December 6,
13. Mayo Clinic. Interstitial cystitis. Symptoms. Web site. http://
www.mayoclinic.org/diseases-conditions/interstitial-cystitis/
basics/symptoms/con-20022439. Published January 2, 2014.
14. Propert KJ, Schaeffer AJ, Brensinger CM, Kusek JW, Nyberg
LM, Landis JR. The intersitial cystitis data base study group:
results of longitudinal follow-up of the interstitial cystitis data
base cohort. J Urol. 2000;163(5):1434-1439.
15. Mayo Clinic. Interstitial cystitis. Complications. Web site. http://
www.mayoclinic.org/diseases-conditions/interstitial-cystitis/
basics/complications/con-20022439. Published January 2, 2014.
16. Clemens JQ, Markossian T, Calhoun EA. Comparison of eco-
nomic impact of chronic prostatitis/chronic pelvic pain syn-
drome and interstitial cystitis/painful bladder syndrome.
Urology. 2009;73(4):743-746.
17. Anger JT, Zabihi N, Clemens JQ, Payne CK, Saigal CS, Rodri-
guez LV. Treatment choice, duration, and cost in patients with
interstitial cysitits and painful bladder syndrome. Int Urogynecol
J. 2011;22(4):395-400.
18. Nickel JC, Teichman JMH, Gregoire M, Clark J, Downey J.
Prevalence, diagnosis, characterization, and treatment of prosta-
titis, interstitial cystitis, and epididymitis in outpatient urological
practice: The Canadia PIE Study. Urology. 2005;66(5):935-940.
19. Barr S. Diagnosis and manageent of interstitial cystitis. Obstet
Gynecol Clin North Am. 2014;41(3):397-407.
20. Hanno PM, Erickson D, Moldwin R, Faraday MM. Diagnosis
and treatment of interstitial cystitis/bladder pain syndrome:
AUA guideline amendment. J Urol. 2015;193(5):1545-1553.
21. Hurst RE, Roy JB, Min KW, et al. A deficit of chondroitin
sulfate proteoglycans on the bladder urothelium in interstitial
cystitis. Urology. 1996;48(5):817-821.
22. Interstitial Cystitis Association. Causes of IC. Web site. http://
www.ichelp.org/about-ic/causes-of-ic/. Published November 25,
2010. Accesed July 1, 2015.
23. Mayo Clinic. Interstitial cystitis. Causes. Web site. http://www.
mayoclinic.org/diseases-conditions/interstitial-cystitis/basics/
causes/con-20022439. Published January 2, 2014. Accessed July
8, 2015.
24. Rourke W, Khan SAA, Ahmed K, Masood S, Dasgupta P, Khan
MS. Painful bladdder syndrome/interstitial cystitis: aetiology, eva-
luation and management. Arch Ital Urol Androl. 2014;86(2):
126-131.
25. Fiehn O, Kim J. Metabolomics insights into pathophysiological
mehcanisms of interstitial cystitis. Int Neurourol J. 2014;18(3):
106-114.
26. Phatak S, Foster HE Jr. The management of interstitial cystitis:
an update. Nat Clin Pract Urol. 2006;3(1):45-53.

27. Interstitial Cystitis Association. IC Treatments. Web site. http://
www.ichelp.org/diagnosis-treatment/treatments/. Published Jan-
uary 15, 2013. Accessed July 1, 2015.
28. Bosch PC, Bosch DC. Treating interstitial cystitis/bladder
pain syndrome as a chronic disease. Rev Urol. 2014;16(2):
83-87.
29. Mayo Clinic. Interstitial cystitis. Treatments and drugs. Web
site. http://www.mayoclinic.org/diseases-conditions/interstitial-
cystitis/basics/treatment/con-20022439. Published January 2,
30. Janssen Pharmaceuticals. Elmiron-100 MG (Pentosan Polysul-
fate Sodium) capsules prescribing information. Web site. www.
orthoelmiron.com/sites/default/files/assets/elmiron.pdf#zoom
¼100. Updated August 2012. Accessed July 29, 2015.
31. Simon M, McClanahan RH, Shah JF, Repko T, Modi NB. Meta-
bolism of [3 H]pentosan polysulfate sodium (PPS) in healthy
human volunteers. Xenobiotica. 2005;35(8):775-784.
32. Hwang P, Auclair B, Beechinor D, Diment M, Einarson TR.
Efficacy of pentosan polysulfate in the treatment of of interstitial
cystitis: a meta-analysis. Urology. 1997;50(8):39-43.
33. Jhang J-F, Kuo H-C. Novel treatment of chronic bladder pain
syndrome and other pelvic pain disorders by Onabotulinumtox-
inA injection. Toxins. 2015;7(6):2232-2250.
34. Schurch B, de Seze M, Denys P, et al. Botulinum toxin type a is a
safe and effective treatment for neurogenic urinary incontinence:
results of a single treatment, randomized, placebo controlled 6-
month study. J Urol. 2005;174(1):196-200.
35. Daifotis AG, Weir EC, Dreyer BE, Broadus AE. Stretch-induced
parathyroid hormone-related peptide gene expression in the rat
uterus. J Biol Chem. 1992;267(33):23455-234458.
36. Yamamoto M, Harm SC, Grasser WA, Thiede MA. Parathyr-
oid hormone-related protein in the rat urinary bladder: a
smooth muscle relaxant produced locally in response to
mechanical stretch. Proc Natl Acad Sci U S A. 1992;
89(12):5326-5330.
37. Torday JS, Rehan VK. Exploiting cellular-developmental evolu-
tion as the scientific basis for preventive medine. Med Hypoth-
eses. 2009;72(5):596-602.
38. Tao YX, Heit M, Lei ZM, Rao CV. The urinary bladder of a
woman is a novel site of luteinizing hormone-human chorionic
gonadotropin receptor gene expression. Am J Obstet Gynecol.
1998;179(4):1026-1031.
39. Zhou XL, Lei ZM, Rao CV. Functional importance of urinary
bladder luteinizing hormone/human chorionic gonadotropin
receptor gene expression. J Soc Gynecol Invest. 1999:6(suppl
1):Abstract 731.
40. Schwalenberg T, Stolzenburg JU, Ho TP, et al. Enhanced urothe-
lial expression of human chorionic gonadotropin beta (hCGbeta)
in bladder pain syndrome/interstitial cystitis (BPS/IC). World J
Urol. 2012;30(3):411-417.
41. Pierce JG, Parsons TF. Glycoprotein hormones: strucutre and
function. Annu Rev Biochem. 1981;50:465-495.
42. Frtiz MC, Speroff L. Endocrinology of Pregnancy. In: Clinical
Gynecologic Endocrinology and Infertility. Philadelphia, PA:
Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011:
269-330.
43. Lapthorn AJ, Harris DC, Littlejohn A, et al. Crystal structure of
human chorionic gonadotropin. Nature. 1994;369(6480):
455-461.
44. Lei ZM, Rao CV. Endocrinology of the trophoblast tissue. In:
Becker K, ed. Principles and Practice of Endocrinology and
Metabolism. Philadelphia, PA: Lippincott Williams & Wilkins;
2001: 1096-1102.
45. Rao CV. Differential properties of human chorionic gonadotro-
pin and human luteinizing hormone binding to plasma mem-
branes of bovine corpora lutea. Acta Endocrinol (Copenh).
1979;90(4):696-710.
46. Rao CV. An overview of the past, present, and future of non-
gonadal LH/hCG actions in reproductive biology and medicine.
Semin Reprod Med. 2001;19(1):7-17.
47. Rao CV, Lei ZM. The past, present and future of nongonadal
LH/hCG actions in reproductive biology and medicine. Mol Cell
Endocrinol. 2007;269(1-2):2-8.
48. Rahman NA, Rao CV. Recent progress in luteinizing hormone/
human chorionic gonadotrophin hormone research. Mol Hum
Reprod. 2009;15(11):703-711.
49. Rao CV. Uphill battle: the saga of hCG research that led to a
paradigm shift. Indian J Med Res. 2014;(140 suppl):S3-S5.
50. Rao CV. Paradigm shift on the targets of hCG actions. In: Cole
L, Butler S, eds. Human Chorionic Gonadotropin. 2nd ed. Lon-
don, UK: Elsevier Limited; 2015:141-147.
51. Rao CV, Ticconi C. Why does human chorionic goando-
tropin have such a broad regulatory roles in the body and
are they totally unexpected? J Reprod Health and Med. 2015;
1(1):1-3.
52. Rao CV. There is no turning back on the paradigm shift on the
actions of human chorionic gonadotropin and luteinizing hor-
mone. J Reprod Health Med. 2016;2:4-10.
53. Singh GS, Tu LM, Gordon DA, Moma S, Whitmore KE. Inter-
stitial cystitis and pregnancy. Web site. http://www.auq.org/
1997/12.html. Published 1997.
54. Erickson DR, Propert KJ. Pregnancy and interstitial cystitis/
painful bladder syndrome. Urol Clin North Am. 2007;34(1):
61-69.
55. Johnson K. Interstitial cystitis symptoms stable or better in
pregnancy. Medscape. Web site. http://www.medscape.com/
viewarticle/813719. Published November 1, 2013. Accesed
July 8, 2015.
56. Interstitial Cystitis Association. Pregnancy & IC. How preg-
nancy affects IC. Web site. http://www.ichelp.org/about-ic/
women/pregnancy-ic/. Published March 25, 2015. Accessed July
8, 2015.
57. Zhou XL, Lei ZM, Rao CV. Treatment of human endometrial
gland epithelial cells with chorionic gonadotropin/luteinizing
hormone increases the expression of cyclooxygenase-2 gene.
J Clin Endocrinol Metab. 1999;84(9):3364-3377.
58. Uzumcu M, Coskun S, Jaroudi K, Hollanders JMG. Effect of
human chorionic gonadotropin on cytokine production from
human endometrial cells in vitro. Am J Reprod Immunol.
2000;40(2):83-88.
59. Srisuparap S, Strakova Z, Brudney A, et al. Signal transduc-
tion pathway activated by chorionic gonadotropin in the
Rao 5

primate endometrial epithelial cells. Biol Reprod. 2003;68(2):
457-464.
60. Perrier d’Hauterive S, Charlet-Renard C, Berndt S, et al. Human
chorionic gonadotropin and growth factors at the embryonic-
endometrial interface control luekemia inhibitory factor (LIF)
and interleukin 6 (IL-6) secretion by human endometrial epithe-
lium. Hum Reprod. 2004;19(11):2633-2643.
61. Akoum A, Metz CN, Morin M. Marked increase in marcophage
migration inhibitory factor syntheisis and secretion in human
endometrial cells in response to human chorionic gonadotropin
hormone. J Clin Endocrinol Metab. 2005;90(5):2904-2910.
62. Berndt S, Perrier d’Hauteruve S, Blacher S, et al. Angiogenic
activity of human chorionic gonadotropin through LH receptor
activation on endothelial and epithelial cells of the endometrium.
FASEB J. 2006;20(14):2630-2632.
63. Herrmann-Lavoie C, Rao CV, Akoum A. Chorionic gonadotro-
pin down-regulates the expression of the decoy inhibitory inter-
leukin 1 receptor type II in human endometrial epithelial cells.
Endocrinology. 2007;148(11):5377-5384.
64. Paiva P, Hannan NJ, Hincks C, et al. Human chorionic gonado-
tropin regulates FGF2 and other cytokines produced by human
endometrial epithelial cells, providing a mechanism for enhancing
endometrial receptivity. Human Reprod. 2011;26(5):1153-1162.
65. Song XY, Zeng L, Jin W, Pilo CM, Frank ME, Wahl SM. Sup-
pression of streptococcal cell wall-induced arthritis by human
chorionic gonadotropin. Arthritis Rheum. 2000;43(9):
2064-2072.
66. Li N, Shigihara T, Tzioufas AG, Notkins AL, Yoon JW, Jun HS.
Human chorionic gonadotropin prevents Sjogren’s syndrome-
like exocrinopathy in mice. Arthritis Rheum. 2007;56(7):
2211-2215.
67. Rao CV. Potential therapy for rheumatoid arthritis and Sjo¨gren’s
syndrome with human chorionic gonadotropin [published online
ahead of print August 2, 2015]. Reprod Sci. 2015. doi:10.1177/
1933719115597765.
68. Teodorczyk-Injeyan JA, Kellen JA. Chorionic gonadotropin-
induced cell proliferation and polyclonal immunoglobulin synthesis
in human mononuclear cells. Biomed Pharmacother. 1988;42(1):
49-53.
69. Kornyei JL, Lei ZM, Rao CV. Human myometrial smooth mus-
cle cells are novel targets of direct regulation by human chor-
ionic gonadotropin. Biol Reprod. 1993;49(6):1149-1157.
70. Tang B, Gurpide E. Direct effect of gonadotropin on deciduali-
zation of human endometrial stroma cells. J Steroid Biochem
Mol Biol. 1993;47(1-6):115-121.
71. Ambrus G, Rao CV. Novel regulation of pregnant human myo-
metrial smooth muscle cell gap junctions by human chorionic
gonadotropin. Endocrinology. 1994;135(6):2772-2779.
72. Eta E, Ambrus G, Rao CV. Direct regulation of human myome-
trial contractions by human chorionic gonadotropin. J Clin
Endocrinol Metab. 1994;79(6):1582-1586.
73. Han SW, Lei ZM, Rao CV. Up-regulation of cyclooxygenase-2
gene expression by chorionic gonadotropin during the differen-
tiation of human endometrial stromal cells into decidua. Endo-
crinology. 1996;137(5):1791-1797.
74. Han SW, Lei ZM, Rao CV. Treatment of human endometrial
stromal cells with chorionic gonadotropin induces their mospho-
logical and functional differentiation into decidua. Mol Cell
Endocrinol. 1999;147(1):7-16.
75. Lei ZM, Taylor DD, Gercel-Taylor C, Rao CV. Human chorio-
nic gonadotropin promotes tumorigenesis of choriocarcinoma
JAr cells. Placenta. 1999;20(1):147-159.
76. Horiuchi A, Nikaido T, Yoshizawa T, et al. HCG promotes pro-
liferation of uterine leiomyomal cells more strongly than that of
myometrial smooth muscle cells in vitro. Mol Human Reprod.
2000;6(6):523-528.
77. Kayisli UA, Selam B, Guzeloglu-Kayisli O, Demir R, Arici A.
Human chorionic gonadotropin contributes to maternal immu-
notolerance and endometrial apoptosis by regulating Fas-Fas
ligand system. J Immunol. 2003;171(5):2305-2313.
78. Hamada AL, Nakabayashi K, Sato A, et al. Transfection of
antisense chorionic gonadotropin ß gene into choriocarcinoma
cells suppresses the cell proliferation and induces apoptosis. J
Clin Endocrinol Metab. 2005;90(8):4873-4879.
79. Cannon JD, Cherian-Shaw M, Chaffin CL. Proliferation of rat
granulosa cells during periovulatory interval. Endocrinol. 2005;
146(1):414-422.
80. Dos Santo E, Dieudonne M-N, Leneveu M-C, Pacquery R, Ser-
azin V, Giudicelli Y. In vitro effects of chorionic gonadotropin
hormone on human adipose development. J Endocrinol. 2007;
194(2):313-325.
81. Fluhr H, Carli S, Deperschmidt M, Wallwiener D, Zygmunt M,
Licht P. Differential effects of human chorionic goandotropin and
decidualization on insulin-like growth factors-I and –II in human
endometrial stromal cells. Fertil Steril. 2008;90(4 suppl):
1384-1389.
82. Kane N, Kelly R, Saunders PT, Critchley HO. Proliferation of
uterine natural killer cells is induced by human chorionic gona-
dotropin and mediated via the mannose receptor. Endocrinology.
2009;150(6):2882-2888.
83. Kajihara T, Uchino S, Suzuki M, Itakura A, Brosens JJ, Ishihara
O. Human chorionic gonadotropin confers resistance to oxida-
tive stress-induced apoptosis in decidualizing human endome-
trial stromal cells. Fertil Steril. 2011;95(4):1302-1307.
84. Bourdiec A, Shao R, Rao CV, Akoum A. Human chorionic
gonadotropin triggers angiogenesis via the modulation of endo-
metrial stromal cell responsiveness to interleukin 1: a new pos-
sible mechanism underlying embryo implantation. Biol Reprod.
2012;87(3):66.
85. Bourdiec A, Calvo E, Rao CV, Akoum A. Transcriptome anal-
ysis reveals new insights into the modulation of endometrial
stromal cell receptive phenotype by embryo-derived signals
interleukin-1 and human chorionic gonadotropin: possible invol-
vement in early embryo implantation. PLoS One. 2013;8(5):
e64829.
86. Bourdiec A, Bedard D, Rao CV, Akoum A. Human chorionic
gonadotropin regulates endothelial cell responsiveness to inter-
leukin 1 and amplifies the cytokine-mediated effect on cell pro-
liferation, migration and the release of angiogenic factors. Am J
Reprod Immunol. 2013;70(2):127-138.

87. Davis JS, West LA, Farese RV. Effects of luteinizing hormone
on phosphoinositide metabolism in rat granulosa cells. J Biol
Chem. 1984;259(24):15028-15034.
88. Guderman T, Birnbaumer M, Birnbaumer L. Evidence for dual
coupling of the murine luteinizing hormone receptor to adenylyl
cyclase and phosphoinositide breakdown and Ca2þ
mobilization.
J Biol Chem. 1992;267(7):4479-4488.
89. Leung PC, Steele GL. Intracellular signaling in the gonads.
Endocr Rev. 1992;13(3):476-498.
90. Shi QJ, Lei ZM, Rao CV, Lin J. Novel role of human chorionic
gonadotropin in differentiation of human cytotrophoblasts.
Endocrinology. 1993;132(3):1387-1395.
91. Ryu KS, Gilchrist RL, Koo YB, Ji L, Ji TH. Gene, interation,
signal generation, signal divergence and signal transduction of
the LH/CG receptor. Gynaecol Obstet. 1998;60(suppl 1):
S9-S20.
92. Choi JH, Wong AS, Huang HF, Leung PC. Gonadotropins and
ovarian cancer. Endocr Rev 2007;28(4):440-461.
93. Lei ZM, Yang M, Li X, Takikawa O, Rao CV. Upregulation of
placental indoleamine 2,3-dioxygenase by human chorionic
gonadotropin. Biol Reprod. 2007;76(4):639-644.
94. Banerjee P, Sapru K, Strakova Z, Fazleabas AT. Chorionic gona-
dotropin regulates prostaglandin E synthase via a phosphatidy-
linositol 3-kinase-extracellular regulatory kinase pathway in a
human endometrial epithelial cell line: implications for endome-
trial responses for embryo implantation. Endocrinology. 2009;
150(9):4326-4337.
95. Ge YC, Li JN, Ni XT, et al. Cross talk between cAMP and p38
MAPK pathways in the induction of leptin by hCG in human
placental syncytiotrophoblasts. Reproduction. 2011;142(2):
369-375.
96. So K-H, Kodithuwakku SP, Kottawatta KSA, et al. Human chor-
ionic gonadotropin stimulates spheroid attachment on fallopian
tube epithelial cells through the mitogen-activated protein kinase
pathway and down-regulation of olfactomedin-1. Fertil Steril.
2015;104(2):474-482.
97. Schumacher A, Brachwitz N, Sohr S, et al. Human chorionic
gonadotropin attracts regulatory T cells into the fetal-maternal
interface during early human pregnancy. J Immunol. 2009;
182(9):5488-5497.
98. Tsampala M, Gridelet V, berndt S, Foidart JM, Geenen V, Per-
rier d’Hauterive S. Human chorionic gonadotropin: a hormone
with immunological and angiogenic properties. J Reprod Immu-
nol. 2010;85(1):93-98.
99. Schumacher A, Heinze K, Witte J, et al. Human chorionic gona-
dotropin as a central regulator of pregnancy immune tolerance. J
Immunol. 2013;190(6):2650-2658.
100. Rao Ch V, Li X, Manna SK, Lei ZM, Aggarwal BB.
Human chorionic gonadotropin decreases proliferation and
invasion of breast cancer MCF-7 cells by inhibiting NF-
kappaB and AP-1 activation. J Biol Chem. 2004;279(24):
25503-25510.
101. Toth P, Li X, Rao CV, et al. Expression of functional human
chorionic gonadotropin/human luteinizing hormone receptor
gene in human uterine arteries. J Clin Endocrinol Metab.
1994;79(1):307-315.
102. Toth P.Clinical data supporting the importance of vascular LH/
hCG receptors of uterine blood vessels. Semin Reprod Med.
2001;19(1):55-61.
103. Chiang G, Patra P, Letourneau R, et al. Pentosanpolysulfate
inhibits mast cell histamine secretion and intracellular calcium
ion levels: an alternative explanation of its beneficial effect in
interstitial cystitis. J Urol. 2000;164(6):2119-2125.
104. Chiang G, Patra P, Letourneau R, et al. Pentosanpolysulfate
(Elmiron) is a potent inhibitor of mast cell histamine secretion.
Adv Exp Med Biol. 2003;539(pt B):713-729.
105. Parsons CL, Forrest J, Nickel JC, et al. Effect of pentosan poly-
sulfate therapy on intravesical potassium sensitivity. Urology.
2002;59(3):329-333.
106. Sadhukhan PC, Tchetgen MB, Rackley RR, Vasavada SP, Liou
L, Bandyopadhyay SK. Sodium pentosan polysulfate reduces
urothelial responses to inflammatory stimuli via an indirect
mechanism. J Urol. 2002;168(1):289-292.
107. Parsons C. Successful downregulation of bladder sensory nerves
with combination of heparin and alkalinized lidocaine in patients
with interstitial cystitis. Urology. 2005;65(1):45-48.
108. Hussa RO. Biosynthesis of human chorionic gonadotropin.
Endocr Rev. 1980;1(3):268-294.
109. Policastro P, Ovitt CE, Hoshina M, Fukuoka H, Boothby MR,
Boime I. The beta subunit of human chorionic gonadotropin is
encoded by multiple genes. J Biol Chem. 1983;258(19):
11492-11499.
110. Hoshina M, Boothby M, Boime I. Cytological localization of
chorionic gonadotropin a and placental lactogen mRNAs during
development of the human placenta. J Cell Biol. 1982;93(1):
190-198.
111. McFarland KC, Sprengel R, Phillips HS, et al. Lutropin-
choriogonadotropin receptor: an unusual member of the G
protein-coupled receptor family. Science. 1989;245(4917):
494-499.
112. Loosfelt H, Misrahi M, Atger M, et al. Cloning and sequencing
of porcine LH-hCG recepor cDNA: variants lacking transmem-
brane domain. Science. 1989;245(4917):525-528.
113. Nickel JC, Herschorn S, Whitmore KE, Forrest JB, Hu P, Fried-
man AJ, Baseman AS. Pentosan polysulfate sodium for treat-
ment of interstitial cystitis/bladder pain syndrome: Insights from
a randomized, double-blind, placebo controlled study. J Urol.
2015;193(3):857-862.
114. Parsons CL, Benson G, Childs SJ, Hanno P, Sant GR, Webster
G. A quantitatively controlled method to study prospectively
interstitial cystitis and demonstrate the efficacy of pentosan
polysulfate. J Urol. 1993;150(3):845.
115. Lin J, Lei ZM, Lojun S, Rao ChV, Satyaswaroop PG, Day TG Jr.
Increased expression of luteinizing hormone/human chorionic
gonadotropin receptor gene in human endometrial carcinomas.
J Clin Endocrinol Metab. 1994;79(5):1483-149125.
116. Konishi I, Koshiyama M, Mandai M, et al. Increased expression
of LH/hCG receptors in endometrial hyperplasia and carcinoma
in anovulatory women. Gynecol Oncol. 1997;65(2):273-280.
117. Mandai M, Konishi I, Kuroda H, et al. Messenger ribonucleic
acid expression of LH/hCG receptor gene in human ovarian
carcinomas. Eur J Cancer. 1997;33(9):1501-1507.
Rao 7

118. Casadesus G, Milliken EL, Webber KM, et al. Declines in cog-
nitive performance are associated with increased luteinizing hor-
mone levels in mice. Mol Cell Endocrinol. 2007;269(1-2):
107-111.
119. Arcangeli A, Noci I, Fortunato A, Scarselli GF. The LH/hCG
axis in endometrial cancer: a new target in the treatment of
recurrent or metastatic disease. Obstet Gynecol Int. 2010;2010:
1-5.
120. Gallego MJ, Porayette P, Kaltcheva MM, Bowen RL, Vadakka-
dath Meethal S, Atwood CS. The pregnancy hormones human
chorionic gonadotropin and progesterone induce human
embryonic stem cell proliferation and differentiation into neu-
roectodermal rosettes. Stem Cell Res Ther. 2010;1(4):28.
121. Lin J, Li X, Yuan FP, et al. Genetic ablation of luteinizing
hormone receptor improves the amyloid pathology in a mouse
model of Alzheimer disease. J Neuropathol Exp Neurol. 2010;
69(3):253-261.
122. Cui J, MinerBM, Eldredge JB, et al. Regulation of gene expression
in ovarian cancer cells by luteinizing hormone receptor expression
and activation. Bio Med Central Cancer. 2011;280:1-16.

Online Article

Recommended

Recommended

More Related Content

What's hot

What's hot (19)

Similar to Online Article

Similar to Online Article (20)

More from Ch Rao

More from Ch Rao (9)

Online Article