Article in press

Review article
Luteinizing hormone is a primary culprit in the endometrial carcinoma
development in elderly women
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
1. Introduction
ECs are the most common gynecologic malignancies with a
higher incidence than ovarian and cervical cancers in Western
countries.1–3
Greater than 95% of endometrial carcinomas are
adenocarcinomas.1–3
The incidence increases with age, thus, 80% of
ECs are seen among post-menopausal women.1–3
Caucasian
women are at a greater risk than black, Hispanic, Asian and Pacific
Islanders, but black women are most likely to die from the
disease.4,5
The incidence of EC is on the rise without an increase in
survival rates during the last four decades.4–6
According to some
estimates, there were about 55,000 new cases and 10,000 died
from EC in 2015.4,5
The estimated economic impact of this
malignancy is about $2.6 billion per year.6
EC is a story of two diseases.7,8
While type 1 disease is
diagnosed in pre-menopausal women, type 2 disease primarily
occurs among post-menopausal women.7,8
The tumors from Type
1 disease are of endometriod histology, usually stages 1 or 2 and
have a favorable prognosis. The tumors from type 2 diseases, on the
other hand, have non-endometrial histology, including serous,
clear cell, mucinous and other high-grade tumors. Type 1 disease is
not usually aggressive, well differentiated, estrogen dependent,
contain estrogen, and progesterone receptors (ER and PR), slow to
spread and can be successfully treated with surgery or with
progestins.7,8
Type 2 disease, on the other hand, is aggressive,
poorly differentiated, estrogen independent, do not contain ER or
PR, vascular, spreads outside the uterus and has a poor prognosis
that requires aggressive treatment.7,8
Type 2 ECs show aneuploidy,
p53
mutations, alterations in several genes, including those
involved in cell cycle progression.9–15
Age, obesity, diabetes, reproductive and family history are some
of the risk factors for type 2 EC development.4,5,16–20
The risk is
modulated by the degree of obesity, thus body mass index has a
strong association with an increased risk.4,5,16–20
Type 2 ECs are associated with bleeding and also pelvic pain and
pressure.4,5
Definitive diagnosis is made by endometrial biopsy or
may be suspected by transvaginal ultrasound and then confirmed
by biopsy.4,5
ECs are surgically staged tumors.21
The early stages
(stages I/II) are usually curable with an excellent 5 year survival
rates.21
Stage IV disease, on the other hand, has less than 10%
survival rates at 5 years.21
Based on the scientific data, we suggest
that LH is a culprit in the type 2 EC development in elderly women.
Journal of Reproductive Health and Medicine xxx (2016) xxx–xxx
A R T I C L E I N F O
Article history:
Received 2 May 2016
Accepted 21 June 2016
Available online xxx
Keywords:
Endometrial carcinoma (EC)
type 1 and type 2 EC
Elderly women
Luteinizing hormone (LH)
LH/human chorionic gonadotropin ( hCG)
receptors
Nongonadal LH/hCG receptors
Estrogens
Gonadotropin releasing hormone analogs
A B S T R A C T
Endometrial carcinomas (ECs) are the most common gynecologic malignancies, exceeding the incidence of
ovarian and cervical cancers in elderly women (post-menopausal) in Western countries. Evidence suggests
that it is a luteinizing hormone (LH) dependent disease. ECs overexpress LH/human chorionic gonadotropin
(hCG) receptors as compared with pre and post-menopausal endometria. Activation of the LH/hCG
receptors in primary and immortalized EC cells results in an increased cell proliferation and invasion,
which are mediated by cyclic AMP(cAMP)/protein kinase A (PKA) signaling, require the presence of LH/hCG
receptors, activation of b1 integrin receptors and an increase in the secretion of metalloproteinase-2
(MMP-2) in its active form. In addition to the endometrium, LH actions in the ovaries and adrenal glands
results in an increased secretion of androgens, which are aromatized into estrogens in the adipose and EC
tissues. LH also has direct effects in the pancreas, which results in an increase in insulin secretion, which in
turn can also stimulate ovarian stromal cell proliferation, luteinization, androgens secretion and
aromatization in adipose and EC tissues. LH is further elevated in post-menopausal women who develop EC
as compared with post-menopausal women who do not develop the disease. These findings support
complex network of LH actions that promote EC development in elderly women.
ß 2016 Published by Elsevier, a division of Reed Elsevier India, Pvt. Ltd.
* Tel.: +1 3053480659.
E-mail address: crao@fiu.edu
G Model
JRHM-33; No. of Pages 7
Please cite this article in press as: Rao CV. Luteinizing hormone is a primary culprit in the endometrial carcinoma development in
elderly women, J Reprod Health Med. (2016), http://dx.doi.org/10.1016/j.jrhm.2016.06.001
Contents lists available at ScienceDirect
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journal homepage: www.elsevier.com/locate/jrhm
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It works through a complex network of actions in several organs
including the EC as well as ovaries, adrenals, adipose tissue and
pancreas.
2. Evidence linking LH to EC
Several earlier studies have suggested that LH might be
involved in the development of EC in post-menopausal women,
based on the findings that circulatory LH levels were further
elevated in women who developed EC as compared to those that do
not develop the disease.22–25
This suggestion has been validated by
a study which demonstrated that ECs overexpress LH/human
chorionic gonadotropin (hCG) receptors as compared with pre- and
post-menopausal endometria.26
This study also demonstrated that
the receptor overexpression increased with the stage of the
disease.26
Subsequent studies have confirmed the receptor
presence not only in ECs, but also in primary and immortalized
EC cells.27–35
The receptor expression was higher in carcinomas
than in the surrounding microscopically normal endometrium and
closely linked to aggressive tumor behavior.30
LH was found to be
mitogenic as well as to enhance invasion in primary and
immortalized EC cells.29,31,33
The EC cells that have higher LH/
hCG receptor levels, showed a greater invasive potential when
exposed to exogenous recombinant LH.33
These actions are cAMP/
PKA mediated and require the presence of the LH receptors.31
The
invasion, which is a prerequisite for metastasis, is promoted by an
activation of b1 integrin receptors, with a subsequent increase in
metalloproteinase (MMP-2) secretion in its active form.31
The
mitogenic, invasion enhancing potential and other effects of LH/
hCG have previously been demonstrated in normal cells.36–63
These normal processes may have been amplified in EC, which is a
hallmark feature of all carcinomas.
Circulatory LH appears to drive EC pathogenesis in elderly
women. These levels (total/bioactive) are elevated up to seven fold
in the women who have developed EC than the cohorts who do not
develop EC.22,64
Therefore, LH seems to be an important factor. But
it alone may not be sufficient, as most elderly women with
elevated LH levels do not develop the disease. Therefore, genetic or
epigenetic and other inherent risk factors may also be required.
3. LH actions in EC
LH has several effects in the normal human endometrium
that are relevant to implantation of blastocyst and its
limited invasion into endometrium and pregnancy continua-
tion.39,42–44,46,49–52,54–62,65,66
When some of the normal actions are
dysregulated, the potential exists for LH to initiate malignant
changes that might lead to the development of EC. The LH actions
in normal endometrial cells fall into proliferation, invasion,
angiogenesis, and apoptosis categories.39,42–44,46,49–52,54–62,65,66
Even though, the latter two have not been demonstrated in the
context of EC development, there is a reason to believe that they
may occur. For example, type 2 ECs are highly vascular and the
increased vascularity could come from the LH, which is a
vasoactive hormone in its own right. For example, uterine
vasculature contains LH/hCG receptors and their activation results
in the formation of new blood vessels as well as dilation of the
existing ones.54,67–71
4. LH actions in ovaries, adrenals, adipose tissue, and pancreas
may contribute to the EC development
The mechanism of LH action to induce EC may also involve its
actions in the ovaries, adrenals, adipose tissue, and pancreas,
through functional LH/hCG receptors in these tissues.72–78
The ovaries of post-menopausal women actively secrete
androgens from the stromal cell compartment and LH can
stimulate this secretion.79–95
The ovaries of women with EC are
even more active in androgens secretion than cohorts without
EC.85,89,92–94,96
The increased secretion comes from hyperplasia
and luteinization of stromal cells and greater elevation of LH
levels.22,63,64,96–99
The role of the adrenal glands in EC development is related to
an increase in LH levels, which can stimulate zona fasciculate to
secrete androgens. In fact, (a) age associated increase in LH levels
correlate with an increased adrenal function in post-menopausal
women,100–103
(b) hCG challenge increases adrenal androgens
secretion in older female macaques104
and finally (c) hCG can
stimulate androgens secretion from human adrenal cortical
cells.75
Adipose tissue involvement in EC pathogenesis is related to an
increased aromatization of androgens from adrenals and ovaries,
which is perhaps under LH and/or insulin control. However, there
is no evidence yet for the LH control, but this may not be a far-
fetched possibility, considering that it contributes to the
aromatase regulation in ovaries. Insulin, on the other hand,
seems to be able to regulate aromatase in fat tissue.105
Activation
of LH/hCG receptors has been shown to increase cell proliferation,
differentiation, and leptin secretion from preadipocytes.76
These
actions are mediated by cAMP/PKA independent mitogen
activated protein kinase yet (MAPK)/c-fos signaling.76
Whether
or how these LH actions could contribute to EC pathogenesis is not
known.
The involvement of the pancreas in EC development in post-
menopausal women is related to the hyperinsulinemia, a known
risk factor in type 2 ECs.4,5,106
In fact, EC patients often have
elevated insulin levels and an increased insulin resistance.106
The
higher insulin levels could come from LH stimulation of b-cells of
pancreas.77
However, it is not known whether LH can also
contribute to increased insulin resistance. Nevertheless, the
increased insulin levels can stimulate ovarian stromal cells
proliferation, luteinization, secretion of androgens, and their
aromatization in EC tissue.106–111
Post-menopausal women regardless of EC have elevated
androgen levels.84,92–95,100–102
These elevated levels come from
a secretion from adrenals as well as ovaries, both of which are
stimulated by LH.72,103,104
The androgens are then converted to
estrogens in adipose and endometrial tissues.111–114
This
conversion is increased in post-menopausal women who
develop EC, as compared to those who do not develop the
disease.109,112
These increases likely come from LH and insulin
stimulation because their levels are elevated during EC
pathogenesis64,106
and the tissues themselves contain their
receptors.64,105–107,110,115,116
In fact, insulin can regulate
aromatase in endometrial and adipose tissues.105,111
Whether
LH is also involved is not known. But it is not a far-fetched
possibility. Estrogens formed from androgens result in only a
small increase in circulation, perhaps due to differences in
metabolic clearance rates, conversions to other steroids and the
level and binding capacity of sex steroid binding globulin
(SHBG).92
The increased aromatization in EC tissue and potential
further stimulation by LH and/or insulin could result in a
high local estrogen concentration in the tumor microenviron-
ment. The role of these estrogens is not known, but they are not
likely to induce type 2 EC because the tumors do not contain
ER.1–3
What roles do these estrogens play, remains to be
investigated.
Fig. 1 presents the proposed model on how LH can induce type
2 EC in elderly women. Future research will undoubtedly bring
several modifications to this model.
C.V. Rao / Journal of Reproductive Health and Medicine xxx (2016) xxx–xxx2
G Model

5. Estrogens versus LH
Estrogens are believed to be culprits in type I EC development
through the mitogenic actions.117,118
These actions are antago-
nized by progesterone, which promotes the differentiation of
endometrial epithelial cells.119
Thus, women who regularly
ovulate and produce progesterone rarely get EC.119
When the
cyclicity ceases and the balance tips in favor of estrogens, then
endometrial cells can continue to proliferate unabated, leading to
EC.119
This tipping can also happen in women who take only
estrogen containing birth control pills.120
The antagonism can also
explain why progesterone therapy works for type 1 ECs.119
Estrogens are not likely to be the culprits in type 2 EC
development because their circulating levels are very low and
there are no ER in the tumor. Conversely, LH are not likely to be the
culprits in type I EC development, because its levels are low, except
during a brief periovulatory period. However, LH/hCG receptors,
which are functionally coupled to physiological responses that are
required for pregnancy initiation and maintenance, are present in
endometrium.39,42–44,46,49–52,54–62,65,66
It is only when LH levels
are chronically elevated, followed by some type of dysregulation
which results in the receptor overexpression and perhaps post-
receptor changes, then the LH actions become relevant in type 2 EC
development. The molecular details of this dysregulation remain to
be investigated.
Pre-menopausal women with polycystic ovarian syndrome
(PCOS) have a 3-fold increase in EC risk, which is impacted by
the degree of obesity.121–128
These women have a higher total/
bioactive LH and androgen levels, increased insulin resistance
and low circulating estrogens, especially if they are not
ovulating.129–132
ECs arise from complex or atypical endometrial
hyperplasias in these women.28,123
Both simple and complex
hyperplasias contain higher LH/hCG receptors levels than
normal endometrium and the levels further increase from
simple to atypical hyperplasias.28
It is entirely possible,
therefore, that LH could also be a culprit in the EC development
in PCOS women.
There are two other hyperandrogenic conditions in which EC
risk also increases. One is hyperthecosis and the other is androgen
producing ovarian tumors.133,134
Insulin levels are elevated and
insulin resistance increases in these women.135
Even though ECs of
these women have not been investigated for the presence of LH/
hCG receptors, it is within the realm of possibility that LH could
also be a culprit in EC development in these pre-menopausal
women.
Even though hCG levels, surrogate for LH, are elevated during
pregnancy, they are not likely to cause EC. Quite to the contrary,
the life-time EC risk decreases with each pregnancy.136
This
pregnancy induced protection comes from progesterone, which
induces cell differentiation. Its levels are rather high to begin with
and they keep increasing to even higher levels during the second
half of pregnancy.
Setiwan et al. have suggested that the classification of ECs
requires a change due to a considerable overlap in risk factors for
type 1 and type 2 diseases.137
Moreover, not every women will
have exactly the same time course of hormonal changes as they
approach menopause and beyond. Therefore, we recommend
reclassification based on LH dependency. In the reclassification,
type 1 ECs are LH independent and type 2 ECs are LH dependent.
Estrogens will have different roles in both the diseases. In LH
independent disease, estrogens can initiate the disease through
their mitogenic effects. In LH dependent disease, estrogens have a
secondary role of increasing LH release from anterior pituitary
gland. In addition, elevation of free estrogens, due to a decrease in
SHBG in post-menopausal obese woman, can serve as a further
powerful stimulus for bioactive LH release.138
The same scenario
applies to pre-menopausal obese women with polycystic ovarian
disease.129
In both cases, obesity will be the primary trigger in
inducing the cascade of hormonal changes that are ultimately
responsible for EC development. Obesity is an important health
concern that costs the U.S. economy approximately $69 billion a
year.139
It increases an individual’s risk for many diseases,
including EC and several other forms of cancer.15,139
However,
not all post-menopausal obese women are likely to develop EC, due
Hypothalamus
Anterior
OvariesAdipose
Ɵssue
PancreasAdrenals
Endometrial
carcinoma
GnRH
LH
LH
LH
LH
Androgens Androgens
AndrogensAndrogens Estrogens Insulin
Insulin
LH
Fig. 1. Proposed model of LH induced type 2 endometrial carcinoma in elderly women. In this model, LH is a primary instigator. Besides direct actions in the endometrial
carcinoma tissue, its works through a number of other organ systems and all of which bear down on EC to drive the disease process. The molecular details of many of these
steps are unknown.
C.V. Rao / Journal of Reproductive Health and Medicine xxx (2016) xxx–xxx 3
G Model

to a lack of strong co-existing genetic predisposition and other
inherent risk factors. On the other hand, some post-menopausal
lean women may develop EC, because of the presence of a strong
genetic predisposition and/or the presence of other inherent risk
factors. Therefore, obesity and consequent elevation of LH levels
are important and can only predispose women to develop EC, when
genetic, environmental, life style and reproductive risk factors co-
exist. This reasoning should neither come as a surprise nor solely
applicable to EC. It is also important to point out that non-
hysterectomized post-menopausal women, regardless of obesity,
who take estrogen replacement therapy for the control of their
menopausal symptoms, are at an increased risk to develop EC, due
to incessant stimulation.118,120
6. Mechanism of LH actions in EC
The following mechanisms of action can be envisioned from the
known LH actions in EC, normal endometrial epithelial and in other
cells.36–63
1. LH binds to its cell surface receptors to activate them.
2. The activation results in the generation of second messengers
such as, cAMP/PKA, PKC, MAPK, b catenin/Wnt, and a cross talk
between them.
3. The second messengers can then regulate cyclins, cyclin
dependent protein kinases, b1 integrin receptors, active
metalloproteinase-2 secretion, pro and anti-inflammatory,
and apoptotic molecules, etc.
4. The receptor activation may also lead to other changes such as
the secretion of cytokines, growth factors, and eicosanoids.
5. LH may also modulate the immunity by regulating the immune
cells trafficking and their cytokines secretion in ECs.
All LH actions can be classified into non-genomic as well as
genomic. In both cases, initial cell surface receptor binding of LH is
necessary. After the binding, the non-genomic actions such as,
second messengers’ generation, activation/inactivation of kinases,
phosphorylation/dephosphorylation of proteins, ion flux changes,
etc. will commence. The non-genomic actions will be rapid and
may be required for sustaining the slow genomic actions. Non-
genomic changes can help in the genomic actions of LH, through
phosphorylation/dephosphorylation of transcription factors, their
nuclear import, subsequent binding to cis-acting elements, etc. The
genomic actions can involve up or down regulation of many genes
in the families of cell cycle, cell invasion, growth factors,
oncogenes, tumor suppressors, apoptosis inhibitory, and multitude
of others, whose identity remains unknown.
7. Need for further research
There is an obvious need for a great deal of further research for a
better understanding of the LH actions in type 2 EC development.
This research could focus on answering the following interrelated
questions.
1. What are the triggering factors for the LH/hCG receptor
overexpression in ECs?
2. What are the cellular, genetic and biochemical mechanisms that
LH uses to increase the cell proliferation, invasion, etc. in ECs?
3. Can LH induce EC pathogenesis in the absence of aromatizable
androgens from ovaries and adrenals or their aromatization in
fat and EC tissues?
4. Does LH upregulate aromatase and/or its catalytic activity in
adipose and EC tissues?
5. Can LH also increase the insulin resistance in obese EC patients?
6. How important are the insulin actions in ovarian stroma and in
EC for the disease development?
7. Can LH regulate immune cells migration and their secretion of
cytokines, chemokines, etc. in ECs?
The answers will enrich our understanding of complex basic
cellular, molecular, biochemical and genetic mechanisms that LH
employs to induce EC development. Such an understanding could
provide discovery path for novel therapeutic targets in ECs.
8. Therapeutic possibilities
When an elevated circulatory LH levels are the culprits in type
2 EC development, then the obvious treatment approach will be to
reduce the levels, which can be accomplished by treatment with
gonadotropin releasing hormone analogs (GnRHa). There are a
number of conflicting reports, however, on the success of GnRHa
treatment.140–148
The reported treatment failures could come from
the advanced disease stage, incomplete EC dependence on LH, low
LH/hCG receptor expression, etc. Complicating the interpretation
of the results are the findings that ECs contain GnRH receptors,
which could mediate the direct inhibitory effect of GnRH in
ECs.149–152
However, there is a report showing that GnRH induced
growth inhibition of EC cells does not require its receptors.146
ECs
seem to produce small amounts of hCG and how this production
impacts the EC development and/or its response to GnRHa
treatment remains unknown.34,153
Future therapies worth explor-
ing include, local delivery of pharmacologic LH/hCG receptor
inhibitors, receptor gene silencers, etc.
Conflicts of interest
The author has none to declare.
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