cancers

Review
Hormonal Therapy for Gynecological Cancers: How Far Has
Science Progressed toward Clinical Applications?
Saikat Mitra 1 , Mashia Subha Lami 1 , Avoy Ghosh 1 , Rajib Das 1 , Trina Ekawati Tallei 2,3 , Fatimawali 3,4 ,
Fahadul Islam 5 , Kuldeep Dhama 6 , M. Yasmin Begum 7 , Afaf Aldahish 8 , Kumarappan Chidambaram 8
and Talha Bin Emran 9, *

1 Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh;

saikat-2018926336@pharmacy.du.ac.bd (S.M.); mashiasubha-2018526349@pharmacy.du.ac.bd (M.S.L.);
avoy-2018626384@pharmacy.du.ac.bd (A.G.); rajib-2016714522@pharmacy.du.ac.bd (R.D.)
2 Department of Biology, Faculty of Mathematics and Natural Sciences, Sam Ratulangi University,
Manado 95115, Indonesia; trina_tallei@unsrat.ac.id
3 The University Center of Excellence for Biotechnology and Conservation of Wallacea, Institute for Research
and Community Services, Sam Ratulangi University, Manado 95115, Indonesia; fatimawali@unsrat.ac.id
4 Pharmacy Study Program, Faculty of Mathematics and Natural Sciences, Sam Ratulangi University,
Manado 95115, Indonesia
5 Department of Pharmacy, Faculty of Allied Health of Sciences, Daffodil International University,
Dhaka 1207, Bangladesh; fahadul29-774@diu.edu.bd
6 Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar,
Bareilly 243122, Uttar Pradesh, India; kdhama@rediffmail.com
7 Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha 61441, Saudi Arabia;



ybajen@kku.edu.sa

 8 Department of Pharmacology and Toxicology, College of Pharmacy, King Khalid University,
Citation: Mitra, S.; Lami, M.S.; Abha 62529, Saudi Arabia; adahesh@kku.edu.sa (A.A.); kumarappan@kku.edu.sa (K.C.)
9 Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
Ghosh, A.; Das, R.; Tallei, T.E.;
Fatimawali; Islam, F.; Dhama, K.; * Correspondence: talhabmb@bgctub.ac.bd; Tel.: +880-1819-942214
Begum, M.Y.; Aldahish, A.; et al.
Hormonal Therapy for Gynecological Simple Summary: The most common therapies for severe and recurrent gynecological cancers are
Cancers: How Far Has Science hormone therapy and chemotherapy, and responsiveness to therapy is a key component in prognosis
Progressed toward Clinical and survivability. Hormone therapy has recently been demonstrated to be an excellent cancer
Applications?. Cancers 2022, 14, 759. treatment approach. Hormone treatment for gynecological cancers is taking drugs that decrease
https://doi.org/10.3390/ hormone levels or impede their biological activity, halting or slowing cancer progression. Hormone
cancers14030759
therapy works by suppressing the multiplication of cancer cells triggered by hormones. Hormonal
Academic Editors: Simon Langdon therapy, such as progestogens or tamoxifen, is frequently recommended for patients with hormone-
and Charlie Gourley sensitive recurrent or metastatic gynecological cancers, but response rates and therapeutic effects
are inconsistent. Therefore, we discuss the pathogenesis of gynecological malignancies from the
Received: 30 November 2021
hormonal landscape and the use of hormonal therapies toward clinical applications.
Accepted: 30 January 2022
Published: 1 February 2022
Abstract: In recent years, hormone therapy has been shown to be a remarkable treatment option
Publisher’s Note: MDPI stays neutral for cancer. Hormone treatment for gynecological cancers involves the use of medications that
with regard to jurisdictional claims in
reduce the level of hormones or inhibit their biological activity, thereby stopping or slowing cancer
published maps and institutional affil-
growth. Hormone treatment works by preventing hormones from causing cancer cells to multiply.
iations.
Aromatase inhibitors, anti-estrogens, progestin, estrogen receptor (ER) antagonists, GnRH agonists,
and progestogen are effectively used as therapeutics for vulvar cancer, cervical cancer, vaginal
cancer, uterine cancer, and ovarian cancer. Hormone replacement therapy has a high success rate.
Copyright: © 2022 by the authors. In particular, progestogen and estrogen replacement are associated with a decreased incidence of
Licensee MDPI, Basel, Switzerland. gynecological cancers in women infected with human papillomavirus (HPV). The activation of
This article is an open access article estrogen via the transcriptional functionality of ERα may either be promoted or decreased by gene
distributed under the terms and products of HPV. Hormonal treatment is frequently administered to patients with hormone-sensitive
conditions of the Creative Commons recurring or metastatic gynecologic malignancies, although response rates and therapeutic outcomes
Attribution (CC BY) license (https://
are inconsistent. Therefore, this review outlines the use of hormonal therapy for gynecological cancers
creativecommons.org/licenses/by/
and identifies the current knowledge gaps.
4.0/).

Cancers 2022, 14, 759. https://doi.org/10.3390/cancers14030759 https://www.mdpi.com/journal/cancers

Cancers 2022, 14, 759 2 of 26

Keywords: hormonal therapy; gynecological cancers; aromatase inhibitors; anti-estrogen; GnRH agonist

1. Introduction
Cancer is a leading cause of death worldwide. Gynecological cancers are the most
prevalent cancer in women. Cervical cancer is the most common type of gynecological
cancer [1]. Gynecological cancer refers to any cancer that develops in a woman’s repro-
ductive organs. Gynecological cancers can start anywhere in a woman’s pelvis, the area
beneath her stomach, and between her hip bones [2]. Cervical cancer, vulvar cancer, vaginal
cancer, uterine cancer, and ovarian cancer are the five categories of gynecological cancer.
The cervix, the lower and narrow end of uterus, is where cervical cancer develops [3]. The
developing world bears a disproportionately high burden of cervical cancer, accounting for
85% of the approximately 493,000 new cases and 273,000 deaths annually. Cervical cancer
is an issue in areas where most people are underprivileged and women’s socioeconomic
position is low, and ethnicity can also be a risk factor [4]. Cervical cancer is the fourth most
common cancer in women and the fourth leading cause of cancer deaths. Premalignant
cervical intraepithelial neoplasia (CIN) precedes cervical cancer. CINs (CIN1, CIN2, CIN3)
can be efficiently cured by uncomplicated surgery, but they carry a risk of future pregnancy
problems [5]. Ovarian cancer is the most common cause of mortality from gynecological
cancer. Around 70% of patients who have ovarian cancer are diagnosed at stage III/IV
and 75% of these cases deteriorate within two years of first-line therapy, making it unlikely
that they will be cured. Though salvage chemotherapy for recurrent cancer can produce
objective tumor responses, it does not always result in longer progression-free or overall
survival [6,7]. Ovarian cancer is believed to be influenced by the pituitary gonadotropins
follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and by progesterone,
androgens, IGF-I, and estrogens [8].
Uterine cancer, also known as endometrial cancer, starts in the uterus, in the layer of
cells that make up the uterus lining (endometrium) [9]. Endometrial cancer is the sixth
most prevalent cancer in women and the fifteenth most common cancer in the general
population. In 2018, there were around 380,000 new cases [10]. Vaginal cancer has five
subtypes: sarcomas, squamous cell carcinoma, clear cell adenocarcinoma, adenocarcinoma,
and melanoma [11]. The 5-year survival rate for women with vaginal cancer is 49%. If the
cancer is diagnosed early, prior to spreading outside of the vaginal wall, the 5-year survival
rate is 66% [12]. Another type of gynecological cancer is vulvar cancer, which begins in the
vulva. Patients with vulvar cancer have a 5-year survival rate of around 70% [13].
Hormone therapy and chemotherapy are the most common treatments for severe and
recurrent gynecological malignancies, and responsiveness to therapy is a critical factor
affecting prognosis and survival. Hormone therapy has become more frequently used in
recent years as a result of the harsh side effects of chemotherapy. Hormone treatment for
cancer involves taking medications that inhibit the biological activity or reduce the level of
hormones in order to prevent or reduce cancer growth. Hormone therapy either inhibits
the production of hormones or stops hormones from causing cancer cells to multiply and
divide. However, it is not effective against all cancers [14]. The treatment of patients with
gynecological cancers has advanced significantly in recent years [15].
The goal of this study was to convey the current state of gynecological cancer research,
with a focus on hormone therapy. Extensive literature searches and reviews were conducted
in order to determine the pathogenesis and possible therapy of hormones. The aim of this
review is to understand the use of hormones in the treatment of gynecological cancers.

2. Pathogenesis of Gynecological Cancers: Hormonal Landscape

2.1. Cervical Cancer
Chronic infection with oncogenic HPV strains is the most important etiological factor
in the development of cervical cancer. The production of two viral oncoproteins, E7 and
Cancers 2022, 14, 759 3 of 26

E6, in parabasal or basal cells, can trigger and maintain neoplastic development [16]. In
pre-invasive squamous cell carcinoma of the cervix, defective cells are restricted to the
epithelium. Cervical intraepithelial neoplasia (CIN) is a noninvasive disorder that is linked
to HPV integration and infection. CIN progresses from early modifications involving
the deeper layers of the epithelium (CIN1) to later stages involving the entire epithelium
(CIN3), which equates to squamous cell carcinoma (Figure 1) [17]. Cervical adenocarcinoma
is a malignant neoplasm involving the cervical glandular epithelium. Adenocarcinoma
exists in a variety of forms; the majority of these have identical etiology and risk factors
to squamous cell carcinoma. Seventy percent of adenocarcinomas are endocervical-type
mucinous adenocarcinomas [18,19].

Figure 1. Pathogenesis of gynecological cancers. Ovarian: Borderline tumors can form from the
ovarian surface epithelium and can develop into low grade serous, endometrioid, clear cell, and
mucinous carcinoma by mutation and alteration of certain genes, e.g., KRAS, BRAF, NRAS, HER2,
CTNNB1, BRAF, ERBB2, ARID1A, PIK3CA, PTEN, HER2, etc. High-grade serous carcinoma is
developed from normal fallopian tube epithelium by the mutation of TP53, CDK12, BRCA1 and 2.
Uterine: Uterine cancer result from TP53, HER2, PI3K, FBXW7, KRAS, PTEN, MLHI, MSH6, Beta-
catenin mutation, and CTNNBI alteration. Vulvar: (uVIN: E6 degrades the tumor suppressor p53;
E7 inactivates the tumor suppressor RB and releases E2F resulting in hyperproliferation.) (dVIN:
Chronic dermatoses, especially Lichen sclerosus and Lichen planus, can progress to dVIN and SCC),
(VIN, vulvar intraepithelial neoplasia). Vaginal: TP53 gene alteration and HPV 16 and 18, etc., are the
importance carcinogenic factors for both HPV-dependent or -independent vaginal cancer. Cervical:
Production of E7 and E6, infection with HPV, CIN progression cause differentiation in squamous
cervical cells and cause invasive adenocarcinoma.

Squamous cell carcinoma is the more prevalent type of cervical cancer. The most preva-
lent cause of cervical cancer, HPV, has a glucocorticoid/progesterone response element
upstream of the common E7/E6 promoter, and progesterone increases the viral DNA’s ca-
Cancers 2022, 14, 759 4 of 26

pacity to transform cells [20–22]. Papillomavirus lesions are aggravated through pregnancy
when progesterone levels are high, and oral contraceptives containing progestogen are a
risk factor for cervical cancer development in HPV-positive individuals. Estrogen activates
human HPV development by upregulating progesterone receptors [22,23]. Although the re-
lationship between estradiol (E2) replacement or selective ER modulator (SERM) treatment
and cervical cancer is contentious [24], the E2-ERα and progesterone–progesterone receptor
(P4-PR) signaling pathways may be implicated in the progression and/or development
of cervical cancer. PR is a ligand-dependent therapeutic target for cervical cancer, much
as it is for endometrial cancer. While PR was produced in 100% of cervical malignancies
in a mouse model, it is produced in only 20–40% of human cervical malignancies [25,26].
Estrogen promotes the growth of E6 and E7 oncogenes, which are thought to be the primary
causes of cervical cancer. Furthermore, ERα and estrogen are essential for cervical carcino-
genesis, while SERMs suppress cervical cancer in HPV-associated cervical cancer mouse
models [27]. Estrogens stimulate cervical carcinogenesis, while progesterone prevents it,
according to data from HPV transgenic mouse models [27,28].

2.2. Ovarian Cancer

The World Health Organization (WHO) histological classification of ovarian cancers is
based on histogenetic principles, and this classification categorizes ovarian tumors based
on their derivation from coelomic surface epithelial cells, germ cells, and mesenchyme (the
stroma and the sex cord). The bulk of malignant ovarian tumors are epithelial ovarian tu-
mors, which are further classified into histological types as follows: carcinosarcoma, mixed
epithelial tumor, undifferentiated carcinoma, and others are examples of serous, mucinous,
endometrioid, clear cell, transitional cell cancers (Brenner tumors), and others [29]. The
most prevalent subtype of ovarian cancer is ovarian serous carcinoma. It manifests as
either low-grade (10% of all serous subtype tumors) or high-grade carcinoma (90% of all
the serous subtype tumors) [30]. Non-epithelial ovarian cancers are a rare but intriguing
type of malignancies that can be particularly difficult to treat due to their non-epithelial
nature. These tumors account for just 10–15% of all ovarian malignancies when taken as a
whole, and they may arise at any age, from infancy to old age. As a general phrase, this
covers a variety of tumors originating from germ cells, sex cord stromal cells, and other
forms of ovarian cancer that are exceedingly uncommon, including small-cell carcinomas
and sarcomas [31]. Conversely, epithelial ovarian tumors can be type I or type II. Examples
of type I epithelial tumors, which grow slowly, are clear cell carcinomas, endometrioid,
and low-grade micropapillary serous carcinomas. Examples of type II epithelial tumors
include high-grade serous carcinoma, undifferentiated carcinoma, and carcinosarcoma.
Borderline tumors begin as ovarian surface epithelium and progress to low-grade serous,
endometrioid, clear cell, and mucinous carcinomas by mutation and change of certain
genes such as KRAS, BRAF, NRAS, HER2, CTNNB1, BRAF, ERBB2, ARID1A, PIK3CA,
PTEN, HER2, and others. In high-grade serous tumors, high-grade serous cancers that arise
from normal fallopian tube epithelium by mutations in TP53 or BRCA1, BRCA2, MLH1,
or MSH2 are thought to be the cause. [32]. Instead of traditional metastasis through the
hematogenous pathway, ovarian cancers metastasize through the peritoneal circulation,
which is involved in the formation of ascites [33].
CA-125 is the most well-known ovarian cancer biomarker. It is a high-molecular-
weight transmembrane glycoprotein that is expressed by coelomic- and Müllerian-derived
epithelia, such as those in the fallopian tube, endometrium, and endocervix [34]. Gene
expression in ovarian cancer shows both how the cancer looks and how it behaves. Clear
cell ovarian cancer is different from other cancers that have a poor prognosis because of
this [35]. The most important thing about any tumor is the combination of genetic changes
that make it grow and make it spread. In this area, ovarian tumors show a lot of different
types. These types of tumors usually have changes in a lot of different genes, such as KRAS,
BRAF, PTEN, TFG-R, and β–catenin [36]. Following the implantation of ovarian cancer
cells, the resulting inflammation causes the release of cytokines such as interleukin (IL)-1, -8,
Cancers 2022, 14, 759 5 of 26

and -6 by peritoneal cells and their associated stromal and immune cells, which drive tumor
angiogenesis and ascites formation by enhancing tumor cell VEGF secretion [37]. In spite of
their variations, each of these ovarian cancer metastatic processes are essentially driven by
cell migration, involving cycles of cell adhesion, actin polymerization, and actomyosin con-
traction [38]. Furthermore, ovarian cancer cells undergo epithelial–mesenchymal transition
driven by ROCK/Rho signaling (Figure 1) [37].
Microfibrillar-associated protein 5 stimulates ovarian cancer motility and metastatic
potential via the Ca2+ -dependent focal adhesion kinase/cAMP response element-binding
protein/troponin C type 1 signaling pathway [39]. Versican is a major upregulated gene
in CAFs that enhances ovarian cancer cell motility and invasion by activating NF-κB
and upregulating the expression of MMP-9, CD44, and hyaluronan-mediated motility
receptors in cancer cells [40,41]. The c-myc oncogene and HER-2/neu are amplified and
overexpressed in 20–30% of epithelial ovarian cancers [42].
Hormone treatment employs the use of prescription medications to prevent or reduce
the action of hormones such as estrogen. This is significant because certain types of ovarian
cancer cells require those hormones to thrive and spread in the body [43]. Exaggerated
stimulation of ovarian tissues by the pituitary gonadotropins follicle-stimulating hormone
(FSH) and luteinizing hormone (LH) leads to ovarian cancer [44]. The longer a woman
is subjected to estrogen, the greater her vulnerability to ovarian cancer is predicted to be.
Because large amounts of estrogen are only present throughout a woman’s reproductive
years, the longer she menstruates, the greater her risk. Childbearing can minimize risk by
giving a woman nine-month “rests” from ovulation during pregnancy, lowering her total
estrogen exposure. When taken for more than three cycles, the medications clomiphene
citrate and pergonal, which are routinely used to treat infertility, appear to raise the risk of
ovarian cancer [45].

2.3. Uterine and Endometrial Cancer

Uterine sarcoma, uterine carcinosarcoma, uterine clear cell carcinoma, and uterine
papillary serous carcinoma are the most prevalent uterine and endometrial cancers. Uterine
cancer has four stages: stage I, in which the cancer is confined to the uterus, stage 2, in
which it has progressed to the cervix, stage III, in which the cancer has migrated to the
vaginal canal, the lymph nodes, or the ovaries, and stage IV, in which the cancer has spread
to the rectum or bladder, or organs other than the uterus, such as the lungs or bones [46].
Endometrial cancer develops when normal endometrial cell development is disrupted.
Endometrial hyperplasia (overgrowth of endometrial cells) is a risk for adenocarcinoma
since hyperplasia can and often does progress to adenocarcinoma; however, cancer can
occur in the absence of hyperplasia [47]. This arises from endometrial hyperplasia brought
on by uncontrolled estrogenic stimulation, and involves the production of progesterone
and estrogen receptors by the estrogen passageway. There are two types of endometrial
carcinoma, estrogen-dependent (type I) or estrogen-independent (type II). Clinical studies
indicate that type I carcinomas are associated with low risk of lymph node metastasis, favor-
able prognosis, early cancer stage at diagnosis, and minimal myometrial invasion, whereas
type II carcinomas are associated with high risk of lymph node metastasis, poor prognosis,
advanced cancer stage at diagnosis, and deep myometrial invasion (Figure 1) [48].
The cancer usually progresses to the serosa and myometrium initially, before progress-
ing to other pelvic and reproductive structures. Whenever the lymphatic system is involved,
the para-aortic and pelvic lymph nodes are typically the first to be affected, however, unlike
in cervical cancer, there is no specific pattern [49]. Endometrial cancer development is
influenced by genes of grade 3. Mutations in a tumor suppressor gene, usually PTEN or
TP53, are common. PTEN has a loss-of-function or null mutation in 50% of endometrioid
malignancies and 20% of endometrial hyperplasias, making the PTEN protein either less
efficient or completely inactive [50]. The mTOR/PI3K pathway is upregulated when PTEN
function is lost, which drives cell proliferation. In endometrial cancers, the TP53 pathway
Cancers 2022, 14, 759 6 of 26

can either be repressed or highly active. Overexpression of a mutant form of TP53 causes
endometrial cancers to become more aggressive (Figure 1) [51].
Loss of function mutations to p27 and PTEN are linked to a favorable prognosis.
In 20% of serous and endometrioid carcinomas, the oncogene Her2/neu is amplified or
overexpressed. Mutations in CTNNB1 (encoding the β-catenin protein) are identified in
14–44% of endometrial malignancies and may suggest a favorable prognosis. In almost
all endometrial cancers involving squamous cells, CTNNB1 alterations are present [51].
Although FGFR2 alterations are present in about 10% of endometrial malignancies, their
impact on prognosis is unknown [50]. SPOP is another tumor suppressor gene that was
reported to be mutated in 8% of serous endometrial carcinomas and 9% of clear cell
endometrial carcinomas [52].
Distinct mutations are associated with type I and II malignancies. ARID1A, which
often carries a point mutation in type I endometrial cancer, is also mutated in approximately
26% of endometrial clear cell carcinomas and 18% of serous carcinomas [53]. In both type I
and II malignancies, PIK3CA is frequently mutated [51]. KRAS is also often mutated [54].
Gonadotropin-releasing hormone analog (GnRHa) was able to inhibit ovarian cancer
cell growth by increasing inositol phosphate levels and initiating protein kinase pathways
such as ERK1/2, and also to stimulate ovarian cancer cell apoptosis by increasing expression
of apoptosis-associated genes and stimulating the Fas system [55]. Inadequate progesterone
leads to unregulated estrogen activity, which can lead to adenocarcinoma and endometrial
hyperplasia [56].

2.4. Vaginal Cancer

Vaginal cancer is a clinically diverse disease. Although HPV is a common cause of
vaginal tumors, there are also carcinogenic mechanisms which are HPV-independent [57].
There are varying stages of histologic differentiation in vaginal cancer: invasive cancer,
potential microinvasive carcinoma, carcinoma in situ, and vaginal intraepithelial neoplasia
(VAIN) (from least to most malignant) [18,58]. TP53 gene alterations are the principal
carcinogenic factor in vulvar cancer and HPV 18 and 16 have a prevalent role in cervical
cancer, whereas vaginal cancer can be caused by either (Figure 1) [59].
Radiation carcinogenesis is a third explanation for the link between vulva or cervix
carcinoma and vaginal cancer [60]. The mechanism by which DES may contribute to
the development of clear cell adenocarcinoma is unknown [61]. In a study of estrogen-
induced maturation arrest of the Müllerian ducts, Robboy et al. proposed in 1984 that
atypical cervical ectropion of the tuboendometrial type and atypical vaginal adenosis may
be precursors to clear cell cancer of the vagina and cervix [62]. Postmenopausal women
who use vaginal estrogen are at the same risk as women who do not use vaginal estrogen
for invasive breast cancer, stroke, blood clots, endometrial cancer, and colorectal cancer [63].

2.5. Vulvar Cancer

Two distinct mechanisms lead to the development of vulvar cancer [64]. The occur-
rence of lichen sclerosis and differentiated vulvar intraepithelial neoplasia (dVIN) is one
factor. This accounts for around 80% of vulvar cancers [65]. dVIN lesions and vulvar
squamous cell carcinomas carry the same TP53 mutations. The second form tends to affect
teenagers who have been infected with high-risk HPV, most commonly HPV 16. The
percentage of vulvar malignancies linked to HPV varies significantly between populations,
spanning from 15–79%. Impaired DNA repair, variations in active repopulation signal-
ing passageways, as well as impaired cell cycle regulation are also possible underlying
causes [66].
EGFR is a transmembrane-receptor tyrosine kinase. When a ligand binds to EGFR, the
receptor is autophosphorylated on tyrosine residues, activating a number of intracellular
channels that can lead to cancer cell proliferation, metastasis, invasion, and promotion
of tumor-induced neovascularization [67]. EGFR overexpression has been reported in
46–72% of patients with vulvar cancer [68]. A negative correlation between HPV status
Cancers 2022, 14, 759 7 of 26

and EGFR amplification suggests that EGFR copy number increases play a role in vulvar
carcinogenesis independent of HPV [69].
Angiogenesis is a critical step in tumor formation and metastatic spread. One of the
most important controllers of this mechanism is the VEGF pathway [70]. In the case of
vulvar cancer, VEGF overexpression is associated with high mortality and poor tumor
distinction [71,72]. In VIN lesions, increased expression had also been reported, alongside
VIN3 expressing much more than VIN1 and VIN2 (Figure 1) [73]. Vulvar cancers are
rarely hormone-dependent tumors [74]. HRT is impartial in endometrial cancer type II,
uterine carcinosarcoma, and adenosarcoma, some forms of ovarian cancer, cervical, vaginal,
and vulvar squamous cell carcinoma, prolactinoma, kidney cancer, pancreatic cancer, and
thyroid cancer [63]. However, tissue-selective estrogen complex incorporating BZA/CE is
a possible menopause therapy for postmenopausal women [75].

3. Hormonal Therapy for Gynecological Cancers

3.1. Hormonal Therapy for Cervical Cancer
Hormonal therapy for cervical cancer has been reported in a variety of experimental
and clinical investigations. Sawaya et al. reported that medroxyprogesterone acetate
at a dose of 2.5 mg/day and oral conjugated equine estrogens at 0.625 mg/day were
administered to 2561 women for two years. This study determined the predictive value
of an abnormal cervical smear in postmenopausal women with recent normal smears. In
the two years after a normal smear, the rate of new cytologic abnormalities was 110 per
4895 person-years (23 per 1000 person-years (95% CI, 18 to 27 per 1000 person years)).
There was one case of mild to moderate dysplasia among the 103 women with documented
histological diagnosis. The positive predictive value of any smear abnormality identified
1 year after a normal smear, therefore, was 0% (CI, 0% to 5.0%) (0 of 78 women); the
positive predictive value of abnormalities found within 2 years was 0.9% (CI, 0.0% to 3.0%)
(1 of 110 women). The findings concluded that the prevalence of cytologic abnormalities
was non-significantly greater in hormone-treated women than in women who were not
treated with hormone [76]. In postmenopausal women undergoing hormone replacement
therapy (HRT), several studies found a significantly lower risk of cervical squamous cell
carcinoma and a slight increase in the risk of adenocarcinoma. There are no indications that
HRT has a negative effect on the oncological outcome of CC, and numerous advantages
have been reported, such as improvement in quality of life and decreased metabolic risk,
leading to the conclusion that HRT should be provided to young survivors of CC for the
management of early menopause [77]. In another clinical trial, 645 women with cervical
cancer aged 40–75 years were medicated with estrogen replacement therapy (ERT) and
followed for ten years. The odds ratio was 0.9 (95% CI: 0.5–1.7). The odds ratios for cervical
cancer decreased with duration of therapy when compared to a control group, decreasing
to 0.6 (95% CI: 0.4–1.1) for timespans shorter than 12 months and 0.5 (95% CI: 0.2–1.0) for
timespans of 12 months or longer. These results indicate that exogenous estrogens may
reduce the incidence of cervical cancer [78]. K14E7 and K14E6 transgenic mice were treated
with 0.15 mL of the ER antagonist Faslodex twice a week for one month, and 1.5 mg of
raloxifene 5 days a week for one month. In this study, raloxifene, an ER antagonist and
selective ER modulator, effectively cleared cancer and precursor lesions in both the vagina
and the cervix [79]. The combination of synthetic estrogen and synthetic progestogen
is effective in treating cervical cancer. After radiotherapy or surgery for stage I or II
cervical cancer, 120 patients received 2 mg chlormadinone and 5 mg dienestrol daily
for five years. The occurrence of cancer relapse was 20% in the group that underwent
hormone treatment [80]. Hormonal therapy (HT) consisting of progesterone, estrogen,
or progesterone and estrogen together was applied in 804 CIN3/CIS cases in peri- and
postmenopausal women and 261 invasive cervical cancer (ICC) cases in three distinct
groups of women who received treatment for different time periods, ≤1, 2–4, and ≥5 years.
The therapy was found to be associated with a lower risk of ICC (HR = 0.5, 95% CI: 0.4–0.8).
The use of HT by peri- and postmenopausal women reduced the risk of ICC substantially.
Cancers 2022, 14, 759 8 of 26

However, estrogen alone was associated with a higher incidence of CIN3/CIS, whereas
coupled HT was associated with a lower incidence of ICC [81].
Certain cervical cancers may respond in a hormone-independent manner to a combina-
tion treatment consisting of triphenylethylene and the antiestrogen medication tamoxifen.
Roig et al. conducted an experiment on 19 patients with invasive cervical cancer and
found that tamoxifen treatment for 10 days at 20 or 40 mg/day resulted in alterations in
growth and distinction levels in some cervical carcinomas [82]. Another study by L. Bigler
found that 10 mg of the antiestrogen medication tamoxifen taken twice a day orally in
34 non-squamous cell carcinoma patients with median age of 49 had an objective response
rate of 11.1% [83]. Another trial studied the use of progestagen mixed oral contraceptives
in 16,573 women who had cervical cancer and 35,509 who did not. The cohort was split
into groups that had used progestagen for fewer than five years, and groups that had
used progestagen for more than five years. The risk of cervical cancer was increased in
the groups with over five years progestagen use [84]. Progesterone, estradiol, and estrone
are essential hormones that are utilized as treatments for cervical cancer. In one study,
11,742 women aged over 18 were subjected to HT, including progesterone (100 pg·mL−1 ),
oestrone (5 pg·mL−1 ), SHBG (20 nmol L−1 ), oestrone sulphate (100 pg·mL−1 ), estradiol
(5 pg·mL−1 ), and DHEAS (10 µg·dL−1 ). After observation for 5–10 years, it was found that
increased plasma levels of progesterone or endogenous estrogens reduced the incidence of
cervical neoplasia (Figure 2) [85].

Figure 2. Hormonal therapies to counter gynecological cancer progression.

Pannoneon and Rauh conducted a clinical trial including 222 women. After treatment
for cervical cancer, 48% of patients received HRT counseling and efforts to decrease in-
equities in the provision of survivorship care were enhanced (Table 1) [86]. Tamoxifen at 0,
Cancers 2022, 14, 759 9 of 26

1, 2.5, 5, 7.5, or 10 µM for a time span of 6 days suppressed the in vitro proliferation of three
cervical carcinoma cell lines generated from uterine cervical carcinoma (ME-180, CaSki,
and HeLa). Progressive cell death and cytotoxicity were found at doses greater than 5 µM.
A dose of 2.5 µM tamoxifen inhibited development by more than 60% in the CaSki cell line,
while 5 µM tamoxifen was cytotoxic [87].

Table 1. Experimental and clinical studies of hormonal therapy to treat cervical cancer.

Name of Formulation
Observation Time Study Model Results References
Hormone Name and Dose
Faslodex twice a Raloxifene, ER antagonist
0.15 mL Faslodex week for a month and selective ER modulator,
K14E7 and K14E6
ER antagonist and 1.5 mg of and raloxifene for efficiently clears cancer and [79]
transgenic mice
raloxifene a month, 5 days a its precursor lesions in both
week the cervix and the vagina
Only 20% and 32%
incidence of cancer
Non-steroid
Dienestrol—1 recurrences and survival
synthetic 120 patients after
tablet (5 mg) and without cancer symptoms
estrogen with 5 years surgery and/or [90]
Chlormadinon—1 was found in 80% and 65%
synthetic radiotherapy
tablet (2 mg) of cases, respectively in the
progestagen
hormonally treated group
and in the control group
Significantly decreased the
risk of ICC in peri- and
HT formulation
261 ICC and 804 postmenopausal women,
(estrogen alone,
CIN3/CIS cases of but menopausal estrogens
Estrogen and progesterone alone, 3 groups (≤1, 2–4,
post- and alone were associated with [81]
progesterone combination of ≥5 years)
perimenopausal an increased risk of
estro-
women CIN3/CIS and combined
gen/progesterone)
HT was inversely associated
with ICC
Exogenous estrogens
ERT — 1–10 years 645 women decreased the risk of [78]
cervical cancer
Oral conjugated
equine estrogens,
Did not significantly affect
Estrogens 0.625 mg/day, plus
2 years 2561 women the incidence of cytologic [76]
progestin medroxyproges-
abnormalities
terone acetate, 2.5
mg/day
Certain cervical carcinomas
had changes in their
Triphenylethylene
10 days (20 or 40 proliferation and
Anti-estrogen antiestrogen 19 patients [82]
mg/day) differentiation levels
tamoxifen
following tamoxifen
administration
The objective response rate
was 11.1%, so tamoxifen
10 mg per orally
Anti-estrogen Tamoxifen 34 patients appears to have minimal [83]
twice a day
activity in non-squamous
cell carcinoma of the cervix
The risk of invasive cervical
Combined oral <5 years and >5 cancer increased with
Progestagen 16,573 women [84]
contraceptives years increasing duration of use,
not for short time use
Cancers 2022, 14, 759 10 of 26

Table 1. Cont.

Name of Formulation
Observation Time Study Model Results References
Hormone Name and Dose
SHBG
(20 nmol·L−1 )
estradiol
(5 pg·mL−1 )
Elevated plasma levels of
Estrone, estradiol estrone
endogenous estrogens or
and (5 pg·mL−1 ) 5–10 years of study 11,742 women [85]
progesterone decrease the
progesterone estrone sulphate
risk of cervical neoplasia
(100 pg·mL−1 )
DHEAS 10 µg·dl−1
and progesterone
100·pg·mL−1
48% patients received
counseling for HRT and
1 January, 2005 to
then improved efforts to
HRT — 31 December 31 222 women [86]
reduce disparities in the
2015
distribution of survivorship
care
In vitro growth of
5% Inhibited cell growth of the
three cell lines
dextran-charcoal cervical carcinoma cell lines;
derived from
ER modulator, treated fetal bovine 2.5 µM tamoxifen induced
6 days carcinoma of the [87]
Tamoxifen serum (D5) and 0, more than 60% growth
uterine cervix
1, 2.5, 5, 7.5, or 10 inhibition where 5 µM
(HeLa, CaSki,
µM tamoxifen tamoxifen was cytotoxic
ME-180)
Contraceptives
(G03A), estrogens
171 (67%) of 257
(G03C), Fewer than half of cervical
women had at least
Estrogens and progestogens 0.5 to 1 year after cancer survivors with
one dispensing of [88]
progestogens (G03D), and diagnosis therapy-induced early
HT (Hor-
progestogens and menopause used HT
monal Therapy)
estrogens in combi-
nation (G03F).
The risk pattern among any
hormonal and combined
30 to 35 µg women aged contraceptive users
Estradiol From 1995 to 2014 [89]
ethinylestradiol 15 to 49 generally increased with
longer duration of use and
declined after stopping

Everhov reported that estrogens, contraceptives, progestogens, and estrogen–progestogen

combination are potent treatments for cervical cancer. In their experiment it was found that
171 (67%) of 257 women had at least one course of HT for half a year to a whole year after the
diagnosis. Slightly less than half of cervical cancer survivors who had therapy-induced early
menopause underwent HT at or close to the suggested dose while reducing the dosage over
time. This implies that HT can be safely given to survivors of cervical cancer [88]. Neverthe-
less, a study of women aged 15–49 taking ethinylestradiol (30–35 µg) between 1995 and 2014
reported that the risk of cervical cancer increased during ethinylestradiol usage and decreased
after cessation [89].

3.2. Hormonal Therapy for Ovarian Cancer

Since the etiology of ovarian cancer is poorly understood, primary prevention efforts
are difficult. According to a meta-analysis of data covering the years 1966–2006, post-
menopausal use of HT increased the risk of ovarian cancer by 30%, and estrogen therapy
Cancers 2022, 14, 759 11 of 26

(ET) alone carried a higher risk than estrogen plus progestin therapy (EPT) [91]. Hormone
treatment for ovarian cancer patients usually consists of a combination of medications
that suppress estrogen levels in the body. Hormone treatment can also be used to raise
progesterone levels, which might inhibit cancer cell growth in some circumstances [44]. The
most common treatments for ovarian stromal tumors are hormone-inhibiting or hormone
medications. Leuprolide and goserelin are two examples of LHRH agonists [92]. Tamoxifen
is a drug that can be used to treat ovarian stromal tumors, but is only utilized in rare cases
to manage advanced ovarian epithelial cancers. The purpose of tamoxifen therapy is to
prevent endogenous estrogens from triggering cancer cell proliferation [93]. Exemestane,
anastrozole, and letrozole are aromatase inhibitors that prevent estrogen synthesis. As they
do not block ovarian estrogen production, they are only useful for reducing estrogen levels
in postmenopausal women (Figure 2) [94].
According to the findings of a global randomized medical study, women who received
estrogen hormone replacement treatment (HRT) following diagnosis with epithelial ovarian
cancer survived longer than women who did not receive estrogen (Figure 2) [95]. The
gonadotropin-releasing hormone analog leuprolide acetate (1 mg) was administered to
23 patients with refractory epithelial ovarian cancer for a minimum of 8 weeks, providing
evidence of antitumor activity against refractory grade 1 epithelial ovarian adenocarci-
noma [96].
When used during CA125 relapses, the aromatase inhibitor letrozole can result in
disease stability and CA125 responses, which are associated with increased ER expression.
Sixty patients were given 2.5 mg letrozole daily for 12 weeks, and the findings showed that
future gynecological cancer investigations might focus on a group of endocrine-sensitive
aromatase inhibitors [97]. Similarly, in a group of 27 patients, letrozole at a dosage of 2.5 mg
once daily was shown to be an effective and safe treatment for recurrent ovarian cancer [98].
Veenhof also noted the efficacy of hormone treatment (Table 2) [99]. Ovarian cancer cells
were shown to be resistant to megestrol acetate, a kind of progestin hormone treatment.
In 72 patients, megestrol acetate 800 mg/day for one month preceded by 400 mg/day as
a maintenance dose was given, with results demonstrating that increasing the dose did
not increase the all-inclusive 10% benefit of hormone therapy for chemotherapy-resistant
ovarian cancer [99].
Another post-M.D. study investigated the effects of progesterone and estrogen on 2933
women with advanced epithelial ovarian cancer. For advanced serous ovarian cancers and
endometrioid carcinoma, ER and PR are predictive indicators. In this study, PR expression
was associated with improved disease-specific survival in endometrioid carcinoma (log-
rank p < 0.0001) and high-grade serous carcinoma (log-rank p = 0.0006), and ER expression
was associated with improved disease-specific survival in endometrioid carcinoma (log-
rank p < 0.0001) [100]. John reported that 12 weeks of treatment with a combination of
2.5 mg twice daily letrozole and 10 mg twice daily everolimus in 20 patients led to a 47%
progression-free survival with tolerable toxicity in individuals with ER-positive recurrent
advanced ovarian cancer [101].
Estrone sulfate (E1S) is used to treat gynecological cancers. After 15 and 60 min
incubation times, 12 postmenopausal women with non-estrogen-producing ovarian tu-
mors were given 20 pmol of [3H] E1S in 100 mL of Tris-HCl. According to Dmitrijus,
in postmenopausal women with non-estrogen-producing ovarian tumors, tumor tissue
transformation of circulating E1S to E2 might be one of the major causes of high S-E2
levels [102]. However, the injection of a single dose of gonadotropin daily in 100 infertile
clomiphene citrate-resistant women with PCOS appeared to be more successful at inducing
ovulation [103].
Cancers 2022, 14, 759 12 of 26

Table 2. Experimental and clinical studies of hormonal therapy to treat ovarian cancer.

Name of Formulation
Observation time Study Model Results References
Hormone Name and Dose
Showed evidence of
antitumor activity
Leuprolide acetate against refractory grade
GnRHa 8 weeks 23 patients [96]
(1 mg) 1 epithelial
adenocarcinoma of
the ovary
Produced disease
Letrozole (2.5 mg stabilization and CA125
Aromatase
daily) at the time 12 weeks 60 patients responses that in turn [97]
inhibitor
of CA125 relapse are linked to higher
levels of ER expression
The aromatase inhibitor
Letrozole at a dose letrozole is an agent
Aromatase
of 2.5 mg once 27 patients with some activity and [98]
inhibitor
a day limited toxicity for
relapsed ovarian cancer.
This study does not
Megestrol acetate: suggest that the overall
800 mg/day for 1 10% benefit from
month followed by hormonal therapy for
Progestin 1 month 72 patients [99]
400 mg/day as chemotherapy refractory
maintenance ovarian cancer will
treatment improve by increasing
the dose
PR expression and ER
expression were
Estrogen,
- 2933 women associated with [100]
progesterone
improved
disease-specific survival
Associated with a
12 weeks of promising (47%)
Oral everolimus
therapy with the progression-free
Aromatase 10 mg daily and
combination of 20 patients survival rate in patients [101]
inhibitor letrozole
everolimus with ER-positive
2.5 mg daily
and letrozole relapsed high-grade
ovarian cancer
Pregnancy and abortion
rate in infertile women
100 infertile
Injection of PCOS receiving
clomiphene-citrate
Gonadotropin of single dose 2003–2008 gonadotropin as a [103]
resistance women
gonadotropin daily treatment for induction
with POCS
of ovulation seems to be
more effective
Conversion of
circulating E1 S to E2 by
the tumor tissue could
20 pmol of [3H] be one important reason
(15 and 60 min) 12 postmenopausal
E1S E1S in 100 mL of for elevated S-E2 levels [104]
incubation time women
Tris-HCl in postmenopausal
women with
non-estrogen-producing
ovarian tumors
Cancers 2022, 14, 759 13 of 26

3.3. Hormonal Therapy for Uterine Cancer

Endometrial cancer is hormone-dependent and is usually preceded by endometrial
hyperplasia. A variety of histologic subgroups have been identified, each with its own
natural history. Although no link has been found between molecular profile, histology, and
hormone response, the underlying biology has been discussed [102]. Hormonal treatments
for endometrial cancer include tamoxifen, GnRHa, aromatase inhibitors (AIs), progestins,
and luteinizing hormone-releasing hormone agonists (LHRH agonists) (Figure 2) [105].

3.3.1. Progestins
Progesterone is an endometrial hormone that inhibits estrogen-induced growth. Though
endometrial neoplasias can decline in response to progestin therapy, this is not always
the case [56]. Progesterone or medications similar to it (progestins) are the most common
hormone treatments for endometrial cancer. The two most commonly used progestins are
megestrol acetate, which is taken as a tablet or a fluid, and medroxyprogesterone acetate,
which is administered as an injection or a tablet. The proliferation of endometrial cancer
cells is slowed by these medications. They have been found to be beneficial in the treat-
ment of women who have endometrial cancer and desire to conceive in the future [106].
Stromal proliferation and the endometrial gland are both reduced by progestins. They
can reduce cyclin-dependent kinase (CDK) expression and increase the expression of an
endogenous CDK inhibitor, p27, preventing CDKs from binding to cyclins and blocking
cell cycle progression, resulting in cell growth suppression. Medroxyprogesterone ac-
etate (MPA) and megestrol acetate (MA) are two of the most regularly utilized progestins
(Figure 2) [107,108].
The use of estrogens for a long duration without progestins, or with the periodic
addition of progestins, increases the risk of endometrial cancer. To reduce the risk of
endometrial cancer associated with estrogen replacement treatment, progestins may need
to be given on a regular basis. Medications containing only estrogens were linked to a
significant increase in endometrial cancer risk, which increased with time and dosage [109].
In order to successfully prevent the heightened risk of endometrial cancer, the progestin in
successive estrogen–progestin replacement treatment must be administered for at least 10
days. The use of a continuous estrogen–progestin combination is also successful. Neither
treatment lowers a woman’s risk of endometrial cancer. The stark difference in the impacts
of progestin usage for 10 or more days (viably 10 days) compared to less than 10 days (viably
7 days) in sequential estrogen–progestin replacement therapy implies that the degree of
endometrial sloughing may be a key factor in assessing endometrial cancer risk [110].

3.3.2. GnRHa
GnRHa is a synthetic GnRH analog with increased half-life, stability, and affinity
for the GnRH receptor. GnRHa competes with GnRH for the binding site of the GnRH
receptor, inhibiting Gn release from the hypophysis and lowering estrogen levels. When
GnRH or GnRHa levels are raised, LH and follicle-stimulating hormone (FSH) levels rise
quickly [111]. It was shown that the GnRH receptor is expressed in approximately 80%
of ESS, implying that GnRHa may be activated by inhibiting these GnRH-R [112]. Fur-
thermore, studies in vivo and in vitro [113,114] showed medication with standard doses of
GnRH agonists, which restrict ovarian estrogen production and pituitary gonadotropin re-
lease, have become a part of early stage EC or pre-cancer (atypical endometrial hyperplasia)
fertility preservation treatment. In severe or recurring EC, typical doses of GnRH agonists
demonstrated only minimal activity. Clinical trials using higher doses or stronger analogs,
such as GnRH-II antagonists, have yet to be conducted. In a phase II study, the GnRH
analog zoptarelin doxorubicin, which is cytotoxic, showed promising effects in patients
diagnosed with recurrent or advanced EC that expressed GnRH-R. The cytotoxic GnRH
doxorubicin compound was no better than free doxorubicin in a phase III study in patients
who had EC with undetermined GnRH-R expression. Future clinical studies focusing on
the GnRH system in EC with better planning and design might be beneficial [115].
Cancers 2022, 14, 759 14 of 26

3.3.3. Aromatase Inhibitors

Aromatase inhibitors, which have been shown to reduce the risk of breast cancer and
levels of endogenous estrogen, may also minimize the risk of developing endometrial
cancer [116]. In almost 60% of uLMS and 80% of LGESS, aromatase was expressed in the
tumor. Aromatase inhibitors also inhibit both the production of estrogen inside tumor cells
and the amount of estrogen in the blood by decreasing the action of aromatase in peripheral
tissues [117,118]. For the clinician, metastatic/recurrent endometrial adenocarcinoma
that is resistant to local or regional treatment or/and chemotherapy is a disheartening
clinical entity. A 58-year-old woman with persistent endometrial cancer that was resistant
to treatment with chemotherapy was effectively treated with anastrozole, an aromatase
inhibitor [119].

3.3.4. SERMs
SERMs are a class of estrogen receptor modulators that include the nonsteroidal drugs
toremifene and tamoxifen, as well as the steroidal fulvestrant. Tamoxifen and toremifene
have been shown to reproduce the action of estrogen in the uterus, stimulating the growth
of endometrial cancer [120,121]. Hormonal treatment has been shown to be beneficial for
metastatic, recurrent, or unresectable low-grade endometrial stromal sarcoma (LGESS)
and hormone receptor-positive (ER+/PR+) uterine leiomyosarcoma (uLMS) with good
tolerance and cooperation. Hormonal medication can be further utilized to preserve fertility
in people with early stage cancer [55]. Low-grade endometrial stromal sarcoma (EES) is
an uncommon tumor with high recurrence but favorable prognosis. Case studies have
documented how these recurrences respond to hormone therapy [122].
Anastrozole (1 mg/day) combined with letrozole (2.5 mg/day) and exemestane
(25 mg/day), both of which are aromatase inhibitors, can be used to treat uterine can-
cer. Patients who had uterine sarcoma, including four patients with ESS and three patients
with LMS, were treated for 29.2 months with this medication, demonstrating that aromatase
inhibitors are helpful in the treatments of ESS [117]. Ramirez treated 81 individuals with
either megestrol acetate (28 patients; 35%), medroxyprogesterone acetate (36 patients; 44%)
or progestins for 24 weeks. Most patients with well-distinguished endometrial cancer are
treated with progestins in a cautious manner. Carcinoma expansion outside of the uterus is
uncommon when response to progestins is not obtained or when the illness recurs [123].
A combination of endogenous or exogenous progestins and estrogen, as well as 160
mg megestrol acetate, is often a beneficial hormonal treatment for uterine cancer. Chu and
Mor reported that ERT may be harmful in patients with low-grade ESS, based on a study of
22 patients, in which hormonal treatment was given for an average of 100 months (range,
2–258). Reduction of ERβ might be a sign of cancer. Adjuvant progestin medication and the
treatment of recurring ESS should indeed be routinely evaluated [124]. In another D. Pink
trial, tamoxifen, ERT, progestin, and aromatase inhibitors were administered together for
durations of 4–164 months in uterine cancer patients. Individuals with a prior record of low-
grade ESS ought not to be medicated with tamoxifen or estrogens, according to the results
of a sarcoma database that was checked for all occurrences of metastatic ESS detected since
1999, including approximately 800 patients. Letrozole and MPA are extremely efficient
and, in most cases, result in long-term illness stabilization [120]. Furthermore, 13 women
were given MA and letrozole for 4–252 months (median 48 months). For patients with
significant recurrent or residual low-grade ESS, hormonal therapy with aromatase inhibitors
and progestin had good reliability and should be regarded as the preferred treatment if
recurring illness cannot be effectively resected [122].
Mizuno reported that medroxyprogesterone acetate (MPA), a treatment that uses
progesterone, was used on 13 successive patients with low-grade ESS for an average of
64 months (ranging from 28–92 months). During the 117-month follow-up timeframe, MPA
treatment for recurrent or residual illness resulted in good control of disease over a period
of 5 years. These findings suggest that MPA treatment could be explored as a possible
treatment for persistent or recurrent low-grade ESS [125]. In another study, 40 patients
Cancers 2022, 14, 759 15 of 26

with advanced uLMS were treated with aromatase inhibitors such as letrozole (in 74% of
patients), exemestane (in 6% of patients), and anastrozole (in 21% of patients), with only 9%
obtaining an objective response. Patients who had ER+ and/or PR+ tumors had a longer
progression-free survival than those with ER− and PR− tumors [126].
Aromatase inhibitors and progestin were used in the case of a 48-year-old woman
identified with stage I ESS. The patient was given three rounds of bleomycin, etoposide,
and cisplatin (BEP), megestrol acetate, and anastrozole, and was monitored for two years.
ESS can be healed with aromatase inhibitors and progestin, according to the findings,
since ESSs with a sex-cord stromal component are hormonally functional [127]. Murphy
reported a patient with an enlarged uterus, dysmenorrhea, and menorrhagia who was
medicated with adriamycin, GnRH agonist, ifosfamide, leuprolide acetate, and cisplatin
and monitored for 15 months following diagnosis. The symptoms of leiomyosarcomas,
such as rapidly increasing uterine masses, pelvic discomfort, and uterovaginal hemorrhage,
are disguised by GnRH medication. However, in this case, the latency in surgical treatment
during GnRH administration resulted in a negative outcome (Table 3) [128].

Table 3. Experimental and clinical studies of hormonal therapy to treat uterine cancer.

Name of Formulation
Observation Time Study Model Results References
Hormone Name and Dose
Patients with
Anastrozole
uterine sarcoma
(1 mg/day),
(4 patients with
Aromatase exemestane Effective in the treatment of
29.2 months ESS, endometrial [117]
Inhibitor (25 mg/day)-1 endometrial stromal sarcomas
stromal sarcoma,
patient, letrozole
and 3 patients
(2.5 mg/day)
with LMS)
When disease recurs,
Medroxy carcinoma extending beyond
progesterone the uterus is rare in patients
acetate (36 patients; reported with
Progesterone 24weeks 81 patients [123]
44%) or megestrol well-differentiated
acetate(28 patients; endometrial adenocarcinoma
35%), progestins who undergo treatment with a
progestational agent
Estrogen, ERT, tamoxifen, MPA and letrozole, in
progestin, progestins, particular, are highly effective
4 to 164 months 800 patients [120]
aromatase aromatase and lead to sustained disease
inhibitors inhibitors control in most cases
Hormonal treatment for
measurable residual or
Megestrol acetate
recurrent low-grade ESS has a
Progestin, (MA), 4+ to 252+ months
high response rate and should
Aromatase Aromatase (median 48+ 11 patients [122]
be considered as the treatment
inhibitors inhibitor months).
of choice for patients in which
(letrozole)
recurrent disease cannot
easily be eliminated
ERT was detrimental in
patients with low-grade
Exogenous or endometrial stromal sarcoma,
endogenous Megestrol acetate 100 months but progestin therapy should
22 patients [124]
estrogen and 160 mg, progestins (range, 2–258) be routinely considered for
progestins adjuvant therapy and for the
treatment of recurrent
endometrial stromal sarcomas
Cancers 2022, 14, 759 16 of 26

Table 3. Cont.

Name of Formulation
Observation Time Study Model Results References
Hormone Name and Dose
MPA therapy might be
Dosing period
considered as a therapeutic
Medroxy 64 months (range
option for residual or
Progesterone progesterone 28–92 months) but 13 patients [125]
recurrent low-grade ESS and
acetate (MPA) follow-up period
perhaps chosen as a
was 117 months
first-line therapy
Aromatase inhibitors
Aromatase achieved objective response in
inhibitors used only 9%. Progression free
were letrozole (in Between 1998 and survival was longer among
Aromatase 40 patients [126]
74% of patients), 2008 patients with ER and/or PR
anastrozole (21%), positive tumors than among
and exemestane (6%) patients with ER and PR
negative tumors
GnRH agonist, A patient with GnRH therapy mask the
leuprolide acetate, menorrhagia, symptoms of
GnRH agonist adriamycin, 15 months dysmenorrhea, leiomyosarcomas, e.g., rapidly [133]
cisplatin, and an enlarging uterine mass, pelvic
ifosfamide etc. enlarged uterus pain, uterovaginal bleeding
Endometrial stromal sarcoma
Three cycles of 48-year-old
with sex-cord stromal
BEP (bleomycin, woman was
component may be
Progestin and etoposide, diagnosed with
2 years hormonally functional and [127]
aromatase cisplatin), stage I
can be cured by treating with
anastrozole and endometrial
progestin and
megestrol acetate stroma sarcoma
aromatase inhibitor
Estrogen, Megestrol acetate A 22-year-old 1 year after the last curettage,
6 months [130]
progesterone and tamoxifen nullipara there is no evidence of disease
Combinations of 9 patients with
Of the 9 patients, 8 (88.9%)
megestrol acetate clinically
achieved complete remission
Estrogen, (160 mg/day), diagnosed
6 months after hormone therapy. All [129]
progesterone tamoxifen endometrial
nine patients have been alive
(30 mg/day), adenocarcinoma
without evidence of disease
and GnRHa stage IA, grade 1
Megestrol
(1-month), This case report signals a
tamoxifen warning that negative clinical
Estrogen, (20 mg/day) and A 36-year-old investigations are not
progesterone, depot leuprolide 6-months nulliparous reassuring for a relapsing [131]
(GnRHa) acetate woman endometrial adenocarcinoma
subcutaneous failing conservative
injection hormonal treatment
(3.75 mg/month)
The quarterly interval for
500 mg of oral
D&Cs was satisfactory with
medroxyproges-
Estrogen, 9 months (range, medroxyprogesterone
terone for 2 women [132]
progestin 3–18 months) treatment, and the patients’
6 months,
desire not to undergo
twice weekly
hysterectomy was met

The efficacy of tamoxifen and megestrol acetate, hormonal treatment with progestins
and estrogen, and GnRHa in uterine cancer is well established (Figure 2). A combination
of GnRHa, tamoxifen (30 mg/day), and megestrol acetate (160 mg/day) was given to
Cancers 2022, 14, 759 17 of 26

9 patients with confirmed stage IA, grade 1 endometrial adenocarcinoma. After treatment
for 6 months, 8 (88.9%) of the 9 patients achieved full recovery. All nine of the patients
have been disease-free for 25–113 (median 69) months since their first diagnosis [129]. In
a study by Fu, a 22-year-old nullipara was treated with tamoxifen and megestrol acetate
for 6 months and 1 year respectively after curettage, and there was no sign of illness [130].
Shih and Jung reported that megestrol (1 month), tamoxifen (20 mg/day), and depot
leuprolide acetate subcutaneous injection (3.75 mg/month) were used to treat a 36-year-
old nulliparous woman with stage IA, grade 1 endometrial cancer. They concluded that
adverse clinical examinations are not encouraging for a recurrent low-grade, early-stage
endometrial adenocarcinoma without conventional hormonal therapy [131]. In two women
of reproductive age, 500 mg of oral medroxyprogesterone was administered for 6 months
and twice weekly for 9 months. With medroxyprogesterone medication, the quarterly
timeframe for D&Cs was acceptable, and the patients’ wishes to avoid hysterectomy were
fulfilled. As a result, the progestin and estrogen-based hormone therapy proved effective
in the treatment of uterine cancer [132]. Endometrial cancer prevalence was reduced
in women on an aromatase inhibitor in comparison to those taking tamoxifen in a peer
group-based, coordinated health care plan system. Aromatase inhibitors may also help to
reduce the risk of tamoxifen-related endometrial cancer. Although the aromatase inhibitor
group had somewhat fewer endometrial malignancies than the no treatment group, further
research is required to evaluate this possible relationship [116].

3.4. Hormonal Therapy for Vaginal Cancer

Vaginal carcinoma is a rare gynecologic malignancy. Surgery can be used to treat
vaginal carcinoma in situ and extremely early stage invasive cancer of the vagina. Radiation
therapy is the usual treatment for women with vaginal cancer. To maintain the structure and
functionality of the vagina, radiotherapy is used as a treatment of last resort for early phase
vaginal cancer. Radiation therapy is used to prevent exenterative surgery, maintain function
and anatomy, and address identified or suspected lymph node metastases in later stages of
vaginal cancer. Estrogen (estrone sulfate) in the form of vaginal promestriene (10 mg soft
vaginal suppository) was given to 17 postmenopausal women daily for one to six months to
treat vaginal cancer. The amount of circulating E1S in extremely symptomatic gynecological
cancer patients was not influenced by vaginal promestriene treatment, although there was
a broad range of individual values before and after treatment [66].
To investigate ElS as a hormonal treatment, the AC-258 cell line and the squamous
vaginal carcinoma cell line EC-82 were treated with ElS and DS (2.25 µCi, 15 µM) for at
least two hours using cell densities of up to 3.2 × 106 cells/mL. In situ estrogen synthesis
from steroid sulfate antecedents in the organs and tissues of and around the reproductive
tract may influence the growth of ovarian and vaginal tumors [134]. Meanwhile, in a
52-week double-blind, randomized, placebo-controlled trial, 205 postmenopausal women
were given an ultra-low-dose 10 µg 17-estradiol vaginal tablet, which did not increase the
incidence of endometrial carcinoma or hyperplasia [135]. A study of 423 women who were
given local estrogen therapy in the form of either estradiol cream (0.1 mg estradiol/g USP)
or estradiol vaginal tablets (10 g) reported that vaginal tablets have higher compliance
than vaginal cream, with the majority of respondents preferring vaginal tablets [136]. The
impact of estrogen on vaginal cancer was also reported in a study in which the estrogen
receptor modulator ospemifene was given for one month to 32 postmenopausal women
receiving surgical intervention, with the results demonstrating that ospemifene improved
the signs of atrophy and cancer by enhancing ERα expression and maturation of the
vaginal mucosa [137]. Bachmann reported that 30 or 60 mg/day ospemifene for 12 weeks
was efficacious for the treatment of vaginal dryness and dyspareunia (that can progress
to vulvovaginal malignancy and atrophy if left untreated) but also better received in
826 postmenopausal women (Table 4) [138].
Cancers 2022, 14, 759 18 of 26

Table 4. Experimental and clinical studies of hormonal therapy to treat vaginal cancer.

Name of Formulation
Observation Time Study Model Results References
Hormone Name and Dose
The level of circulating E1S
was not significantly
Vaginal
affected by vaginal
promestriene
Estrogen (estrone 17 patients (after promestriene treatment, but
10 mg soft vaginal 1–6 months [66]
sulfate) menopause) a wide range of levels was
suppository daily
noted pre- and
for one month
post-treatment in
individual patients
Incubation time for
AC-258 cell line,
at least 2 h and Played a role in the
ElS and DS squamous
E1S with cell number development of tumors of [134]
(2.25 µCi, 15 µM) vaginal carcinoma
up to the ovary and vagina
cells (line EC-82)
3.2 × 106 cells/mL
(n = 205) in a
Ultra-low-dose There was no increased risk
randomized,
10-microgram of endometrial hyperplasia
Estradiol 52 weeks double-blind, [135]
17β-estradiol and carcinoma in
placebo-
vaginal tablets postmenopausal women
controlled trial
Local estrogen There was greater
therapy (LET) in compliance with vaginal
5-week period,
form of estradiol tablets than with vaginal
from 6 March 2012
Estrogen vaginal tablets, 423 women cream; respondents [136]
through
10 µg, estradiol preferred their current
9 April 2012
cream, 0.1 mg treatment with the
estradiol/g USP vaginal tablet
Increased maturation, and
ERα expression of the
vaginal mucosa. These
ER modulator 32 postmenopausal
Estrogen 1 month changes partially explained [137]
(ospemifene) women
the improvement of
symptoms of vaginal
atrophy and cancer
Effective and well tolerated
826 for the treatment of the
Ospemifene 30 or postmenopausal symptoms of vaginal
ER modulator 12 weeks [138]
60 mg/day women were dryness and dyspareunia
randomized associated with
vulvovaginal atrophy over

3.5. Hormonal Therapy for Vulvar Cancer

Jacob reported that HRT with progesterone and estrogen in a population of 7189 women
was not harmful. The majority of vulvar malignancies in this cohort were estrogen-
independent squamous cell carcinomas [139]. The estrogen receptor modulator ospemifene
was found to be helpful for the prevention of vaginal and vulvar cancer and atrophy in
women with dyspareunia in a study of 605 postmenopausal women using oral ospemifene
60 mg/day for 12 weeks [140].
The estrogen receptor modulator bazedoxifene (BZA) was given to 664 postmenopausal
women for 12 weeks at doses of 20 mg/CE, 0.625 mg, 0.45 mg, and 20 mg. BZA/CE was
efficacious in preventing mild-to-advanced VVA and vaginal symptoms. These findings
suggest the use of a BZA/CE-containing tissue-selective estrogen complex as a potential
menopause treatment for postmenopausal women [141]. Conjugated estrogens 0.625 mg
and 0.45 mg BZA 20 mg were administered to 2 groups of 1583 postmenopausal women
and provided endometrial protection without increasing breast pain/density, vaginal bleed-
Cancers 2022, 14, 759 19 of 26

ing, or ovarian cysts after 2 years of observation [75]. Additionally, in 652 symptomatic
postmenopausal women, therapy with BZA/CE for a duration of 12 weeks dramatically
enhanced quality-of-life parameters and attenuated cancer [142]. Following a 12-week
study of 25 women with endometrial biopsies, Mirkin speculated that 4 µg and 10 µg
vaginal estradiol (E2) does not cause endometrial hyperplasia resulting in moderate to
severe dyspareunia, which is also considered to be a symptom of vaginal and vulvar cancer
and atrophy (Table 5) [143].

Table 5. Experimental and clinical studies of hormonal therapy to treat vulvar cancer.

Name of Formulation Observation

Study Model Results References
Hormone Name and Dose Time
Significantly decreased the
proportion of women
receiving at least one HRT
prescription. The majority
Hormone
Estrogen, of vulvar cancers are not
replacement 12 months 7189 women [139]
progesterone estrogen-dependent, and
therapy
the prescription of HRT is
not contraindicated after the
diagnosis of this type
of cancer
Effective for the treatment of
vulvar and vaginal atrophy
Oral ospemifene
ER modulator 12 weeks 605 women and cancer in [140]
60 mg/day
postmenopausal women
with dyspareunia
BZA 20 mg/CE
Healthy Effective in treating
0.625 mg and
ER modulator 12 weeks postmenopausal women moderate to severe VVA [141]
0.45 mg, BZA
(n = 664; aged 40–65 y) and vaginal symptoms.
20 mg
Conjugated estrogens/BZA
Conjugated provides endometrial
1583 and 1583
Estrogen and ER estrogens 0.625 mg protection without
2 years postmenopausal women [75]
modulator and 0.45 mg/BZA increasing breast
respectively
20 mg pain/density, vaginal
bleeding, or ovarian cysts
Postmenopausal,
Shown to significantly
non-hysterectomized
BZA 20 mg/CE improve sexual function
Estrogen and ER women (n = 652) with
0.45 or 0.625 mg, 12 weeks and quality-of-life measures [142]
modulator symptoms of moderate
BZA 20 mg. in symptomatic
to severe vulvar/vaginal
postmenopausal women
atrophy
Because of endometrial
progesterone receptor
expression, vaginal E2
would not be expected to
Vaginal 4 µg and stimulate endometrial
Estradiol 12 weeks 25 eligible women [143]
10 µg estradiol (E2) hyperplasia leading to
moderate to severe
dyspareunia which is a
symptom of vulvar and
vaginal atrophy and cancer
Paroxetine significantly
Selective
7.5 mg oral reduced hot flashes in
serotonin-
paroxetine or 16 weeks 80 women weekly frequency and [144]
reuptake
placebo daily severity in gynecological
inhibitors (SSRIs)
cancer survivors
Cancers 2022, 14, 759 20 of 26

4. Risk Factors Associated with HRT in Gynecological Cancers

Hormone treatment slows or prevents the growth of hormone-sensitive cancers by
interacting with the actions of hormones on breast cancer cells or by limiting the body’s
ability to produce hormones [145]. Postmenopausal women who received “some” estro-
gen treatment are more likely to develop estrogen-receptor and progesterone-receptor
positive breast tumors [146]. The application of antiestrogenic drugs such as nafoxidine
and tamoxifen has shown to be the most effective new hormonal treatment for estrogen
receptor-positive metastatic breast cancer. Both of these medications have anticancer effec-
tiveness similar to other additive hormonal treatments, and they are better tolerated due
to the lack of significant toxicity [147]. The therapeutic uses of aromatase inhibitors (AI)
and GnRH agonists that limit estrogen production, tamoxifen, a selective estrogen receptor
modulator (SERM), and fulvestrant, a selective ER downregulator (SERD) have resulted
in significant improvements in survival outcomes for patients with ER+ breast cancer via
ER-alpha (ESR1) mutation, growth factor receptor signaling, as well as PI3K/Akt/mTOR,
CDK4/6, and epigenetic and immunological checkpoints as resistance mechanisms [148].
HRT may raise the risk of developing heart disease, stroke, and type 2 diabetes and inflam-
matory markers (such as C-reactive protein) [149,150]. HT may decrease stiffness of the
aorta and large arteries in postmenopausal women, with potential benefit for age-related
cardiovascular disorders. The reduction of arterial compliance with age appears to be
altered with hormonal therapy [151].
The effects of hormone treatment against invasive ductal, lobular, and tubular car-
cinoma were typically larger for estrogen-progestagen therapy and lessened with rising
BMI (body mass index) [152]. Tamoxifen use highly increased the incidence of secondary
diabetes, although aromatase inhibitors had no effect on diabetes mellitus in individuals
with initial breast cancer [153]. However, HT is a recognized risk factor for blood clots
like deep vein thrombosis or pulmonary embolism [154]. Moreover, HT also raises liver
disease and unusual vaginal bleeding that has not been reviewed by physicians [155]. The
increased risk is related to how long the HRT is administered, and it falls after the patient
stops taking it [156].

5. Concluding Remarks and Future Directions

HT is a promising therapeutic option for patients with recurring gynecological malig-
nancies, whose primary goal is palliation and life extension (rather than cure). Aromatase
inhibitors can be used for long periods of time with even less cumulative injury as these
inhibitors are usually well tolerated. Previous studies have reported a wide range of
functional properties and response rates. HT is often thought of as “less potent” in com-
parison to chemotherapy, yet it can be just as useful in certain types of gynecological
cancer. Hormone treatment is classified as a “systemic” therapy since it affects the entire
body. In addition to gynecological cancer prevention, HRT has shown potential in treating
postmenopausal symptoms. HRT, such as progestin and estrogen combination therapy or
estrogen monotherapy has been shown in recent trials to benefit postmenopausal women
with osteoporosis as well as some concomitant disorders. HT can stop or slow the growth
of cancer, and reduce the chance that it will return. To promote a better future generation
and healthy life, HT for gynecological illnesses is very important. Further study and clinical
trials should be undertaken to discover new benefits of HT for gynecological cancers.

Author Contributions: Conceptualization, S.M. and T.B.E.; investigation and resources, S.M., M.S.L.,
R.D. and A.G.; writing—original draft preparation, S.M., M.S.L., R.D. and A.G.; writing—review,
updates and editing, S.M., T.E.T., F., F.I., K.D., M.Y.B., A.A., K.C. and T.B.E.; visualization and
supervision, K.D., M.Y.B., A.A., K.C. and T.B.E.; formal analysis, S.M., M.Y.B., A.A., K.C. and T.B.E.;
resources, T.E.T., F., F.I., K.D. and T.B.E.; project administration, T.E.T., F., F.I., K.D. and T.B.E.; funding
acquisition, M.Y.B., A.A., K.C. and T.B.E. All authors have read and agreed to the published version
of the manuscript.
Cancers 2022, 14, 759 21 of 26

Funding: The authors extend their appreciation to the Deanship of Scientific Research at King Khalid
University for funding this work through Research Group (Small) Project number RGP.1/330/42.
Conflicts of Interest: The authors declare no conflict of interest.

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