Uterus-Hormonal Regulation

Tae Hoon Kim and Jae-Wook Jeong, Michigan State University College of Human Medicine, Grand Rapids, MI, United States
© 2018 Elsevier Inc. All rights reserved.

Introduction

The uterus consists of heterogeneous cell types that undergo dynamic changes to support embryo development and implantation.
The mature uterus consists of three tissue layers, the endometrium, myometrium, and serosa. The serosa is a single outer cell layer of
tissue made of epithelial cells that envelop the uterus. The myometrium is the muscular layer, composed of inner circular and outer
longitudinal smooth muscle layers. The endometrium is the most active layer and composed of stroma and epithelial cells (Brody
and Cunha, 1989).
The ovarian steroid hormones estrogen (E2) and progesterone (P4) are essential regulators of uterine functions necessary for
embryo implantation, development, and normal pregnancy, and the balance of these two steroid hormones working cooperatively
is required for the maintenance of a healthy endometrium (Fig. 1) (Dharma et al., 2001; Wood et al., 2007). These steroids act
primarily through their respective cognate nuclear receptors, the progesterone receptor (PGR) and the estrogen receptor (ESR).
E2 stimulates proliferation of both the uterine epithelial and stromal cells in neonatal mice. However, this proliferative action
of E2 is restricted to epithelial cells in the adult mouse uterus (Martin et al., 1973a; Huet-Hudson et al., 1989). In contrast, while
P4 is inhibitory to E2-mediated proliferation of the luminal and glandular epithelial cells, P4, alone or in conjunction with E2, leads
to uterine stromal cell proliferation (Huet-Hudson et al., 1989; Martin et al., 1973b; Paria et al., 1993).
The cross talk between epithelial and stroma cells changes due to P4 and E2 (Franco et al., 2012; Winuthayanon et al., 2010).
These changes are critical for embryo implantation and development. E2 regulates uterine epithelial proliferation unlike P4 which
inhibits the E2-induced proliferation of the epithelium (Martin et al., 1973a,b). P4 inhibits the proliferation via stromal-epithelial
cross-talk. Successful embryo apposition, attachment, and implantation can be established under well-organized uterine receptivity
(Wetendorf and DeMayo, 2012). A defect in maintaining the status of uterine receptivity is the major cause of most pregnancy los-
ses. The ability of ovarian steroids to mediate endometrial proliferation occurs through the ability of hormonal stimulation to regu-
late growth factor communication networks between the uterine stromal and epithelial cells. P4 inhibits E2-stimulated epithelial
cell proliferation in the uterus by the regulation of gene expression in endometrial stromal cells (Rubel et al., 2010).
Inappropriate activation of endometrial proliferation and differentiation by dysregulation of steroid hormones is one of the
major features of uterine disease (Kao et al., 2003). Uterine diseases of the female reproductive tract represent a significant women’s
health problem. Excessive uterine proliferation caused by dysregulation of the steroid hormones results in several uterine diseases
including infertility, endometriosis, and endometrial cancer (Bokhman, 1983; Sherman et al., 1997; Deligdisch and Holinka, 1987;
Kurman et al., 1985). Endometrial cancer is a frequently occurring gynecological disorder (Siegel et al., 2016). Estrogen-dependent
endometrioid carcinoma is the most common type of gynecological cancer. Endometriosis was found in 10% of reproductive-age
women, and 35%–50% of infertile women had endometriosis (Jemal et al., 2006; Eskenazi and Warner, 1997; Bulun, 2009).
Understanding the role of steroid hormone regulation of uterine function is critical in evaluating the pathology of these uterine
diseases.

Progesterone

Progesterone (P4) is one of the major ovarian steroid hormones. P4 is produced by the corpus luteum in the ovaries (Graham and
Clarke, 1997), and its synthesis and secretion are regulated by luteinizing hormone and chorionic gonadotropin during the
menstrual cycle and pregnancy (Graham and Clarke, 1997). P4 is absolutely necessary for uterine implantation, decidualization,
and maintenance of pregnancy (Wetendorf and DeMayo, 2012). Implantation is the most critical step to establish pregnancy in
the uterus. Successful implantation requires the attachment of the embryo to a uterine luminal epithelium and its subsequent

Fig. 1 Steroid hormone regulation of endometrium.

Encyclopedia of Reproduction, 2nd edition, Volume 2 https://doi.org/10.1016/B978-0-12-801238-3.64651-2 305

306 Female Reproductive Tract j Uterus-Hormonal Regulation

invasion into the stromal tissue (Young, 2013). P4 prepares the endometrium to implant the embryo into the uterine epithelium
and maintain the pregnancy after fertilization and implantation (Mote et al., 1999). After implantation, the uterine stroma of the
surrounding implantation site starts to proliferate and differentiate, resulting in decidual cells that support the growth of the embryo
which is known as decidualization (Cha et al., 2012). Importantly, the high level of P4 is maintained to control the generation of
other eggs throughout the pregnancy progression, and to inhibit lactation before birth (Capuco and Akers, 2009).
P4 has an important role in the regulation of the immune and endocrine system, which mediate the role of the trophoblasts at
the implantation site (Drake et al., 2001). Trophoblasts are cells that form the outer layer of a blastocyst which plays a critical role in
embryo implantation and interaction with the decidual cells (Red-Horse et al., 2004). It is reported that P4 increases the cytokines
released by Th2 cells which are dominant within the decidua in early pregnancy, resulting in the maintenance of pregnancy.
Th2-induced cytokines trigger the secretion of hCG from trophoblasts. The secreted hCG leads to P4 production from the corpus
luteum in pregnancy (Drake et al., 2001). This supports the maintenance of pregnancy by P4.

Estrogen

Estrogen (E2) is an imperative hormone that stimulates uterine epithelium capacity and regulates the menstrual cycle. Its interplay
with P4 is critical in the changes of the uterus during pregnancy (Hantak et al., 2014). E2 is highly secreted by ovaries, and secretion
peaks at ovulation and its level is rapidly decreased after ovulation (Burns and Korach, 2012). Before ovulation, E2 plays an impor-
tant in the regeneration and growth of the endometrium. E2 prepares the endometrial tissue to respond to progesterone after ovula-
tion (Groothuis et al., 2007).
The proliferation of the uterine endometrium is triggered by E2. This phenomenon enhances the growth of the endometrium
and increases the uterine weight. E2 also helps the uterine wall to slough off dead tissue during menstruation (Gargett et al.,
2012; Vasquez and DeMayo, 2013). In addition, E2 is the most important hormone in preparation for parturition. E2 stimulates
proliferation in the myometrium, accomplishing the considerable growth that is necessary for the forceful contractions of labor
(Kumar and Magon, 2012; Kota et al., 2013).

Steroid Hormone Receptors

Nuclear receptors are a family of ligand-activated transcription factors that are activated by steroid hormones, such as estrogen and
progesterone, and thyroid hormones, oxysterols and fat-soluble vitamins. After nuclear receptors are activated, their main function
is to regulate gene expression for numerous biological processes including cell proliferation, development, and reproduction as
transcription factors (Tsai and O’Malley, 1994). Nuclear receptors include several distinct modular domains for transactivation
regions (AF-1), DNA-binding domain (DBD) that includes two Zn fingers, ligand-binding domain (LBD) that contributes to inter-
actions of the subset of nuclear receptors on their mode of action, and hormone response elements (HRE) act as binding regions for
steroid hormone receptors (Sever and Glass, 2013).
Steroid hormone receptors, in particular the progesterone and estrogen receptors (PGR and ESR), are important functional regu-
lators of female reproductive biology. PGR and ESR are members of the nuclear receptor superfamily. PGR and ESR1 are expressed
in all compartments of the uterus, and their tight regulation is critical for uterine function (Large and DeMayo, 2012). The steroid
hormones, P4 and E2, exhibit their effects via the progesterone receptor (PGR) and estrogen receptors (ESR). PGR and ESR regulate
the effect of P4 and E2 under physiological conditions, either by activation of P4 or E2 target genes transcription on the uterine
tissues (Li and O’Malley, 2003; Acconcia and Kumar, 2006).
The ovarian steroid P4 mediates its effects through the PGR, which belongs to the nuclear receptor superfamily. As in all
members of this family, the PGR contains modular functional domains. The PGR contains an N-terminal transactivating function
domain (AF-1), a central DNA binding domain, and a ligand binding domain with a second activation domain (AF-2) (Sever and
Glass, 2013). The PGR is found as two major isoforms, PRA and PRB, which are expressed from one gene with two alternative trans-
lation start sites. The PRB isoform contains an additional 164 amino acids at the N-terminus and a third activation domain (AF-3)
(Wierman, 2007).
The importance of PGR in uterine function was demonstrated with the genetic ablation of PGR in mice (PRKO), which results in
pleiotropic reproductive defects including those of sexual behavior, gonadotropin regulation, anovulation, lack of decidualization,
and mammary branching morphogenesis. Ablation of PGR does not impact uterine development or morphology. However, abla-
tion of PR renders the mouse uterus incapable of supporting embryo implantation (Lydon et al., 1996).
The total level of PGR and the ratio of PR-A/PR-B varies in reproductive tissues. The function of PR-A and PR-B were studied
using an animal mouse model. Ablation of PRA alone (PRAKO) demonstrated that PRA is the major mediator of P4 signaling
in the mouse reproductive tract, and these mice show similar ovarian and uterine abnormalities seen in the PRAKO mice. In addi-
tion, the PRAKO mice, in which PRB is solely expressed, show an abnormal P4-induced proliferative effect on the epithelium in
opposition from its normal antiproliferative inhibition of E2. Ablation of the PRB isoform (PRBKO), although exhibiting mammary
morphogenesis defects, did not display any uterine phenotype, and the mice were fertile (Vasquez and DeMayo, 2013). The mice
with ablation of specific PR-A and PR-B demonstrated that PR-A plays a crucial role in the mouse uterus and PR-B is mediated in
mammary gland maturation (Kariagina et al., 2008).
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ESR1 and ESR2 are expressed in distinct tissues. ESR1 is mainly expressed in the mammary glands, pituitary, hypothalamus,
ovarian theca cells and uterus, while ESR2 is detected in the ovarian granulosa cells, lung and prostate. ESR1 expression is regulated
by very firm hormonal and temporal control, indicating spatial and temporal roles during implantation. Specific ablation of epithe-
lial ESR1 in the murine uterus led to infertility due to dysregulated estrogen signaling. It was discovered that epithelial ESR1 has an
important role in the regulation of epithelial apoptosis, while stromal ESR1 mediated E2-induced epithelial proliferation (Vasquez
and DeMayo, 2013; Wierman, 2007; Deroo and Korach, 2006).
Interactions with many transcriptional coregulators are required to activate PGR and ESR1 signaling. These coactivators or core-
pressors make large complexes that engage in the remodeling of chromatin through histone post-translational modifications, and
link transcription factors to the basal transcriptional RNA polymerase II machinery for all subsequent genomic actions (Szwarc et al.,
2015). Steroid receptor coactivator (SRC) family members (SRC-1, SRC-2, SRC-3) interact with nuclear receptors and enhance target
gene transcription. The function of steroid receptor coactivator is associated with regulation of steroid hormone signaling. Many
studies have found that steroid receptor coactivator plays an important role in the regulation of reproductive biology including
ovulation, implantation, and parturition. Furthermore, dysregulation of steroid receptor coactivator actions led to infertility, cancer,
and endometriosis (Szwarc et al., 2014; Losel and Wehling, 2003).

Nongenomic Actions of Steroid Hormones

According to the classical model (genomic action) of steroid action, in the absence of P4 and E2 hormones, PGR and ESR1 are local-
ized in the cytoplasm. To make an activated state of PGR and ESR, after hormone binding, it undergoes a conformational change
and translocates to the nucleus where it regulates target gene expression. In contrast, a nongenomic action is distinguished from
genomic steroid actions (Fig. 2). These responses are known as “non-classic,” “non-genomic” or “extra-nuclear” steroid effects.

Fig. 2 Steroid hormone actions. Modified from Boonyaratanakornkit, V. and Edwards, D. P. (2007). Receptor mechanisms mediating non-genomic
actions of sex steroids. Seminars in Reproductive Medicine 25(3), 139–153.
308 Female Reproductive Tract j Uterus-Hormonal Regulation

Nongenomic actions are (1) observed in some cell types without a nucleus such as erythrocytes and platelets; (2) not blocked by
inhibitors of transcription; (3) very rapid actions; (4) initiated by membrane-steroid signaling (Losel and Wehling, 2003).
In the uterus, this transcriptional activation can also occur in a ligand independent fashion as a result of phosphorylation of
PGR and ESR1. In addition, PGR and ESR1 interact with src to activate the MAP kinase pathway to regulate target genes during
the regulation of nuclear receptors target genes, and coregulator complexes are formed (Vasquez and DeMayo, 2013; Tsai and
O’Malley, 1994; Li and O’Malley, 2003; Szwarc et al., 2014). Nongenomic E2 plays a crucial role in the regulation of endometrial
inflammatory response during implantation, pregnancy, and menstruation by modulating gene expression and secretion that
support fertilization and embryo viability. Furthermore, nongenomic E2 exhibits effects on the calcium-signaling pathway that
are associated with muscle contraction in the reproductive tract (Solar and Velasquez, 2013).
Three membrane progesterone receptors are identified: mPRa, mPRb, and mPRg in a variety of species. mPRs modulate the
activity of various signal transduction cascades binding P4, including modulation of ERK1/2 or p38 MAPKs, inhibition of cAMP
production. Furthermore, these membrane proteins are also associated with eliciting contraction in parturition (Losel and Wehling,
2003).

Dysregulation of Steroid Hormone Signaling

E2 induces proliferation of epithelial cells in the uterus, while P4 has an inhibitory effect on E2-induced proliferation (Martin et al.,
1973a,b). An unbalancing of this steroid signaling causes infertility and several gynecological diseases such as endometriosis, endo-
metrial cancer, and leiomyomas. The major pathologic phenomenon of uterine disease is the dysregulation of ovarian steroid
hormones across epithelial proliferation and apoptosis in the uterus (Bokhman, 1983; Sherman et al., 1997; Deligdisch and
Holinka, 1987; Kurman et al., 1985). These uterine diseases display characteristic dysregulation of PGR and ESR expression and
of their downstream target genes in their pathologies. All of these disorders have been mainly associated with increased E2 sensi-
tivity or dysregulation of P4. Loss of functioning P4 signaling leads to P4 resistance, either at the level of the PGR or its target genes,
and it can lead to the disruption of the critical epithelial-stromal cross talk. The antagonistic effect of P4 on E2 forms the rationale
for progestin-based therapeutics for endometrial cancers (Benshushan, 2004; Minaguchi et al., 2007; Hahn et al., 2009; Yamazawa
et al., 2007). However, many studies indicate limiting the use of P4 therapy due to its low response rates (Ramirez et al., 2004; Park
et al., 2012; Decruze and Green, 2007; Randall and Kurman, 1997; Kim et al., 1997). Resistance to P4 treatment, via loss of proges-
terone receptors (PGR) or its signaling pathways, is a major hurdle in the treatment of many of diseases in the endometrium of
women including endometriosis and endometrial cancer (Al-Sabbagh et al., 2012; Burney et al., 2007; Soyal et al., 2005; Attia
et al., 2000).
The endometrium undergoes well-defined and regulated gene expression in preparation for implantation. The timing of endo-
metrial receptivity coincides with the down-regulation of epithelial ESR1 in normal mid-secretory endometrium. P4 and PGR are
essential for successful embryo implantation, but there is a shift in PGR out of the epithelium to the stromal compartment that also
occurs during the implantation. Persistence of ESR1 and PGR in the glandular epithelium is associated with infertility and suspected
implantation defects. Infertility is major reproductive health problem. Assisted reproductive technologies (ART) is the gold standard
tool to help couples who had pregnancy failure due to an implantation defect (Levgur et al., 2000). P4 supplementation has been
studied to improve the success of ART (Allahbadia, 2015; Practice Committee of American Society for Reproductive Medicine,
2008). P4 supplementation is associated with improvement of implantation and pregnancy rates, compared to treatment with
placebo or no treatment. In addition, any type of P4 supplementation administration enhanced pregnancy outcomes in ART cycles
(van der Linden et al., 2015).
The efficacy of P4 supplementation in women with unexplained recurrent miscarriages were investigated, considering its role in
pregnancy (Hussain et al., 2012; El-Zibdeh and Yousef, 2009). Several clinical trials were studied to improve the pregnancy outcome
that is associated with P4 supplementation in unexplained infertility or recurrent pregnancy loss patients (El-Zibdeh and Yousef,
2009; Clifford et al., 1997). A study on 203 women who had experienced at least three unexplained recurrent miscarriages was
randomized to receive P4 supplementation for examining the miscarriage rate. The incidence of miscarriage rate was lower in
the P4 treated group than in the untreated group when compared with historical data. The majority of cited clinical trials revealed
that P4 supplementation can have beneficial effects in women with otherwise unexplained recurrent miscarriages (Hussain et al.,
2012). P4 supplementation can be administrated via vaginal suppositories, intramuscular injection or oral intake (Walch and
Huber, 2008).
Endometrial cancer is the most often diagnosed disease of the female uterus in the United States and the incidence of new cases
has increased over the past several decades (Siegel et al., 2016). The major treatment for endometrial cancer is surgery to remove the
uterus and cervix (called a hysterectomy) (ACOG Committee, 2009; Temkin et al., 2016). Although most cases of endometrial
cancer are diagnosed in post-menopausal women, 5% of women have endometrial cancer before age 40 and 20%–25% are
diagnosed with endometrial cancer before menopause (Pellerin and Finan, 2005). Furthermore, the number of endometrial cancer
diagnoses in younger patients will continue to increase due to an increase of known endometrial cancer risk factors such as obesity,
high blood pressure, and diabetes mellitus (Chassot et al., 2002; Charytan et al., 2012; Varon and Marik, 2008).
A steroid hormone imbalance could lead to aberrant endometrial proliferation and endometrial cancer. P4 therapy has been
used in the conservative endocrine treatment of endometrial complex atypical hyperplasia and early endometrial cancer in young
women with a desire to maintain their fertility (Hahn et al., 2009; Kim et al., 2013). P4 and its analogues can have an effect on
 Female Reproductive Tract j Uterus-Hormonal Regulation 309

suppression of endometrial cancer proliferation (Yang et al., 2011). However, more than 30% of patients fail to respond to
progestin due to de novo or acquired P4 resistance (Decruze and Green, 2007). Further, P4 resistance is seen in a wide variety
of endometrial diseases such as infertility, endometriosis, as well as endometrial cancer. Therefore, the identification of P4-regulated
signaling pathways in the uterus is crucial for understanding the impairments that underlie disruption of steroid hormone control
of uterine cell proliferation and differentiation.
Endometriosis is defined as the presence of endometrial cells outside of the uterine cavity. Endometriosis is one of the most
common causes of chronic pelvic pain, dysmenorrhea, and infertility, affecting 10% of all reproductive age women and 35%–
50% of infertile women (Eskenazi and Warner, 1997; Bulun, 2009; Kim et al., 2013; Johnson and Hummelshoj, 2013; Burney
and Giudice, 2012). Surgical excision of lesions and hormonal suppression are the current gold standards of therapy, but both
approaches are associated with a significant risk of morbidity and a high incidence of relapse (Bulun, 2009; Sinaii et al., 2002).
Therefore, identification of mechanisms involved in the pathogenesis of endometriosis and development of novel therapies are crit-
ical. Endometriosis is an estrogen (E2) dependent, inflammatory condition. Pro-inflammatory cytokines contribute to chronic
pelvic pain and inflammation, the latter a key factor for pathogenesis and pathophysiology (Bulun, 2009).
Adenomyosis is a common benign gynecological disease caused by the presence of endometrial glands and stroma found within
the myometrium (Tamai et al., 2005; Ferenczy, 1998). The prevalence of adenomyosis ranges from 10% to 66% in women diag-
nosed at the time of hysterectomy (Vercellini et al., 2006). Adenomyosis is one of the most common causes of menorrhagia,
dyspareunia, dyschezia, dysmenorrhea, and chronic pelvic pain (Levgur et al., 2000). Most women are not diagnosed until later
stages of the disease and invasive surgical intervention is required for severely symptomatic women due to less of an effect of phar-
macological therapy (Vercellini et al., 2006).

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