Side effects of different agents of GnRH analogues in Men and Women

Side effects of different agents of GnRH analogues in Men and Women

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Side effects of different agents of GnRH analogues in Men and Women

Abstract

Background: GnRH antagonists and agonists are considered short peptide analogues associated

with GnRH that may cause different profound inhibitions of both androgen and estrogen

synthesis. There are various adverse effects associated with the use of GnRH analogues in

treating different types of diseases. This meta-analysis was done to compare different side effects

of the GnRH analogues in men and women applied in the treatment of various diseases.

Objective: There have been various effects associated with the use of GnRH analogues in

different groups, such as children, women, and men, especially for different ages. The adverse

effects have been indicated for the diverse groups around the world when GnRH analogues are

used. The objective of this meta-analysis was to determine the different effects associated with

the use of GnRH analogues which include Leuprolide, Histrelin, Goserelin, Triptorelin, and

Degarelix because each GnRH analogue has its effects to the patients.

Methods: This meta-analysis used online databases such as Google Scholar, PubMed, Web Med,

Cochrane, and Drug bank to find the different data and RCT studies used in the previous studies

on the side effects of varying GnRH analogues. The trials of the data obtained were limited for

the years between 1995 to July 2015. This was achieved by the use of terminologies related to

GnRH analogues. The search was done for different parts of the world that use GnRH analogues

in their treatment, such as the USA, Asia, and Europe. This meta-analysis used the fixed model

in the analysis to get results on the levels of the side effects of GnRH analogues. The study

sample that was used in this analysis was 1719 participants.

Side effects of different agents of GnRH analogues in Men and Women

Conclusions: From the analysis, it was possible to determine the various side effects associated

with the use of GnRH analogues, especially the GnRH agonists and the antagonist Degarelix.

From the analysis, it was possible to discover that agonists and antagonists' use maintains

estrogen levels in women and testosterone in men when its use is limited within one year. The

analysis found that some adverse effects such as erectile dysfunction, hot flushes, and

cardiovascular effects were prone in the patients put under the GnRH analogue treatments. There

was a statistical significance showing the adverse effects associated with the application of

GnRH analogues in advanced prostate cancer treatment.

Side effects of different agents of GnRH analogues in Men and Women

Abbreviations

GnRH- Gonadotropin-Releasing Hormone

GnRHR- Gonadotropin-Releasing Hormone Receptors

FSH-follicular stimulating hormone

LH- luteinizing hormone

ART-Assisted Reproductive Technology

CPP- Central Precocious Puberty

ADT- androgen-deprivation therapy

APC- Advanced Prostate Cancer

Side effects of different agents of GnRH analogues in Men and Women

1: Introduction

Background

GnRH antagonists and agonists are considered short peptide analogues associated with

GnRH that may cause different profound inhibitions of both androgen and estrogen synthesis.

They are also mostly used as androgen deprivation therapies of advanced prostate cancer.

Besides, these analogues are also used in the treatment of benign conditions that are responsive

to hormonal inhibition, which includes infertility, endometriosis, precocious puberty, and uterine

fibroids. The most known agonists of GnRH include leuprolide, triptorelin, histrelin, and

Goserelin (Irahara, 2005). Several analogues of the GnRH have been mostly associated with

transient serum enzyme elevations during treatment procedures. However, none of these

analogues is causing any clinically significant injuries to the liver.

The GnRH is any decapeptide mostly produced in the hypothalamus. It acts on the GnRH

receptors that are found on gonadotropin cell surfaces located in the pituitary gland. This

hormone stimulates the release of both FSH and LH. In turn, this stimulates the male testis to

produce and release the testosterone, stimulating the female placenta and ovary to produce and

release estrogen. Circulation of the estrogen in females and testosterone in men helps regulate

the synthesis of GnRH since its production is mostly in a pulsatile way(Irahara, 2005). An

increase in sex hormones in both men and women is considered a result of GnRH agonists'

infusions since they lead to increased stimulation. However, when non-pulsatile hormone

stimulation increases, the production, synthesis, and release of FSH and LH are inhibited,

resulting in a decline in testosterone levels and estrogen production. GnRH analogues have been

mostly used to module the synthesis of sex hormones because they are more potential in
Side effects of different agents of GnRH analogues in Men and Women

sustaining actions than the native decapeptide hence being used for the sex hormone modulation.

The degarelix analogue act differently from the other analogues because it is mostly an

antagonist of the gonadotropin receptors found in the pituitary. It inhibits the direct synthesis and

release of FSH and LH. This inhibition is done without the typical initial surge of the GnRH

agonists. The GnRH agonists and the antagonists are considered to have similar effects and

efficacy; however, there is a difference that comes in between the two where there is a quick

onset, and the first surge in the release of the sex hormone lacks for the pure antagonist(Irahara,

2005).

According to (Kumar et al.., 2014), GnRH, with its various analogues, has been widely

applied in clinical practices since 1971 when they were identified and synthesized. Their

discovery was based on the systematic consequences of discovering both the amino acid

sequence of the GnRH, which led to the creation of antagonistic and agonistic GnRH analogues

with several scientific clinical perspectives. The native GnRH has been mostly applied to induce

ovulation in females because they can stimulate gonadotrophs of the anterior pituitary. However,

the GnRH agonists are considered to be more potent, making them longer half-life than the

native GnRH(Kumar & Sharma, 2014). The GnRH agonists generate the first stimulation of

pituitary gonadotrophs that leads to the secretion of both LH and FSH and the production of

gonadal response. This gonadal response is then followed by the inhibition and down-regulation

of the pituitary-gonadal axis. Comparing both the GnRH antagonists and GnRH agonists, the

GnRH antagonists mostly cause suppression to the pituitary gonadotropin through creating

competition in the GnRH receptor hence preventing the initial stimulation of the agonists(Kumar

et al.., 2014). According to (Kumar et al.., 2014), patients can have a fast and easily predictable

pituitary-gonadal axis recovery if the GnRH antagonist treatment is discontinued.

Side effects of different agents of GnRH analogues in Men and Women

In understanding the issue of ovary stimulation, the continuous use of GnRH in specific

doses to the patients at a frequency which is similar to the endogenous release results to the

stimulation of the ovaries which in turn induces ovulation in anovulatory situations, such as

when patients are having polycystic and hypothalamic amenorrhea ovarian diseases (Markussis,

1993). Investigations have been done under Assisted Reproductive Technology(ART) to

understand how agonists releasing gonadotropin hormone and ovarian stimulation gonadotropins

stimulate ovulation (Fraser, 1997). This combination is also referred to as "Superovulation

therapy," It is most effective in women who have inadequate responses to stimulation of

gonadotropin or in women who get early ovulation. The various benefits of this type of therapy

are that they suppress the release of the endogenous gonadotropin, prevent early ovulation, and

the number of canceled cycles is decreased, a high number of oocytes are recovered, and also

they lead to increased pregnancy rates. Currently, when women’s regular menstrual cycles have

delayed follicular phases or changes in gonadotropin-stimulated periods, the GnRH antagonists

are being used to stimulate ovulation (Fraser, 1997).

There are various side effects of the GnRH analogues. These include various hypogonadism

symptoms such as fatigue among the patients, the patients gaining weight, fluid retention in the

bodies, patients having hot flashes, and the males having erectile dysfunctions associated with

low libido. According to (Maillefert JF, 1994), effects such as osteoporosis, weight gain, diabetes

worsening conditions, and metabolic abnormalities can be brought about by the long term

therapies. Also, there are rare but serious adverse effects that may occur to patients under

pituitary adenoma, which worsens their prostate cancer conditions caused by the surge in

testosterone with an initial injection of both pituitary apoplexy and GnRH agonists. According to

(DeLeve, 2007) there are clinical instances associated with GnRH agonists such as histrelin and
Side effects of different agents of GnRH analogues in Men and Women

Goserelin that lead to liver injuries. However, there is no clear evidence that supports the

indication that there is any cross-sensitivity among the different GnRH analogues which causes

damages to the liver despite the structural similarity of the GnRH analogues (DeLeve, 2007).

GnRH agonists have always been applied in the treatment of endometriosis, which has

been a reproductive condition for many years. It is associated with patients experiencing severe

pelvic pains and increased infertility rates(Bergqvist et al., 2000). There has been a high

dependence on both estrogen and retrograde menstrual bleeding for the treatment of

endometriosis, which has led to the development of medical treatment principles that aim to

induce inhibition of menstruation and ovarian suppression in women. GnRH agonists can

desensitize and stimulate the regulation of the pituitary GnRH receptors, which results in a

reduction in the concentration circulation of serum gonadotropin, and also this inhibits ovarian

steroidogenesis. Due to this consequential amenorrhea and anovulation, the GnRH agonists have

been used in endometriosis treatment. This treatment has been essential because it has been

causing suppression to the pain symptoms, especially within two months of the therapy

(Bergqvist et al., 2000).

According to (Beyer et al., 2011), in the treatment of endometriosis, GnRH agonists are

more productive. They are also useful in treating different disorders, such as uterine

leiomyomata advanced prostate cancer, and precocious puberty. The GnRH agonists help reduce

the spread of the endometrial lesion. They also minimize pelvic pain occurrence related to

endometriosis. Such agents are considered to be associated with different psychiatric and

physical side effects. There is always a consistent adverse side effect of these agents together
Side effects of different agents of GnRH analogues in Men and Women

with ovarian suppression physiological effects, including dryness in the vagina, headaches, and

vasomotor instability(Beyer et al., 2011).

Triptorelin

Triptorelin is a GnRH agonist, which in women inhibits the synthesis of estrogen. In

contrast, in men, it inhibits the synthesis of testosterone, and it is mostly applied when treating

advanced prostate cancer. During therapy, it is associated with a low rate elevation of transient

serum enzyme; however, it has not been sufficiently linked to cases of clinically induced acute

liver injuries (LiverTox, 2018 ). Triptorelin is considered a decapeptide GnRH analogue that

mostly acts on the pituitary, which leads to the synthesis and release of both LH and FSH.FSH

and LH are the gonadotropins that stimulate the male testes to produce testosterone, and also in

the female, they stimulate estrogen synthesis. Triptorelin, together with other GnRH agonists,

causes the release of gonadotropin; however, this then brings about down-regulation of the

hormones, resulting in a decline in the production of both testosterone and estrogen. Triptorelin

is considered to be more effective in managing advanced prostate cancer when used alone or

combined with other anti-androgens; hence, it is regarded as useful as surgical castration

(LiverTox, 2018 ). Triptorelin and other GnRH analogues are believed to cause profound

hypogonadism, which is chemical castration. Triptorelin has various commonly known side

effects: hot flashes, males having erection dysfunctions, vaginal dryness in women, diarrhea,

nausea, people gaining weight, fluid retention in the bodies, and depression. Triptorelin's severe

side effects include pituitary apoplexy, the patients experiencing hypertension reaction, and

when used for a more extended period, weight gain, diabetes, osteoporosis, and metabolic

changes in the patient's body (LiverTox, 2018 ).

Side effects of different agents of GnRH analogues in Men and Women

Degarelix

Degarelix is a GnRH antagonist that is parentally administered, and it effectively blocks

the production of androgen and is also applied in the treatment of PC. This therapy is mostly

associated with an elevation in serum enzymes during therapy sessions (Boccon-Gibod, 2011).

Degarelix is a GnRH synthetic decapeptide antagonist that helps in blocking GnRH from

stimulating the production of LH and FSH by the pituitary gland, hence leading to a decrease in

the synthesis of testosterone in men and the synthesis of estrogen in women ovaries. Degarelix is

said to be more palliative in APC treatment, where it has equivalent efficacy when crelated to the

GnRH agonists, such as Goserelin and leuprolide. Degarelix does not cause any initial increase

in the synthesis of testosterone compared to the GnRH agonists, which increase testosterone

synthesis. The use of in the United States was approved in 2008, and currently, it is limited to

advanced prostate cancer treatment. The dosage for degarelix is considered 240mg at the initial

stage, and during the maintenance stage, the dosage is given to the patients in 80mg every 28

days (Boccon-Gibod, 2011). Degarelix's side effects include hot flashes, males having erection

dysfunctions, diarrhea, nausea, people gaining weight, fluid retention in the bodies, and

depression. In contrast, Degarelix's severe side effects include the patients experiencing

hypertension reaction, pituitary apoplexy, and when used for a more extended period, diabetes,

weight gain, osteoporosis, and body metabolic changes (Boccon-Gibod, 2011).

Goserelin

Goserelin is a GnRH agonist which parenterally administered where it causes estrogen

inhibition, the production of androgen production, and is predominantly used in prostate cancer
Side effects of different agents of GnRH analogues in Men and Women

treatment. It has always been associated with the elevation of serum enzymes during therapies

but is not fully linked to causing injuries to the liver during the clinical instances. Goserelin is

considered a GnRH synthetic decapeptide analogue that acts as a partial agonist of the

gonadotropin receptors in the pituitary that are used to regulate the secretion of both LH and

FSH. Such gonadotropins make the male testes, and the female ovaries produce and secrete

testosterone and estrogen, respectively. The continued receptor occupancy causes Down-

regulation in the production of both FSH and LH by Goserelin, decreasing testosterone and

estrogen levels. When Goserelin is either used alone or when combined with other different anti-

androgens, it is more palliative in the treatment of APC.

Its use was approved in 1989 in the United States, and it is currently widely used since it

is thought to be an essential adjuvant therapy in APC management. Besides, Goserelin is also

being used when treating advanced breast cancer in women and even in the treatment of benign

conditions that are hormonally sensitive such as endometriosis. In men, Goserelin has been

predominantly used in treating prostate cancer, while women are mostly used when treating certain

types of breast cancer and other uterus disorders, i.e., endometriosis. In women, Goserelin is used to

treat abnormal uterine bleeding in women with thin uterus lining. Goserelin is almost similar to any

natural hormones that are made by the human body, i.e., it is similar to Luteinizing hormone-

releasing hormone (LHRH), where it helps to decrease testosterone hormone produced in men and

decreasing estrogen hormone which is produced in women. Due to these effects, the rapid growth of

cancer cells is either stopped or slowed. Also, the growth of the uterine tissue that depends on the

hormones is slowed; hence their growth and spread in the body are controlled.
Side effects of different agents of GnRH analogues in Men and Women

Within the market, Goserelin uses Zoladex as a brand name, and it is put to the patients in the

form of implants where the patients are given 3.6mg every four weeks or 10.8 mg for every

twelve weeks. Like the other GnRH agonists, Goserelin has various commonly known side

effects that include hot flashes, males having erection dysfunctions, diarrhea, nausea, and people

gaining weight, body fluid retention, and depression. When it is used for a more extended period,

it might lead to weight gain, diabetes, osteoporosis, and metabolic changes in the patient's body,

which is typical for all GnRH agonists.

Histrelin
Histrelin is a GnRH agonist that acts as a potent gonadotropin inhibitor when

administered as an implant that is important to deliver a continuous therapeutic dose. This

administration is then followed by the stimulation phase, which increases the LH and FSH

circulation levels, leading to an increase in the concentration of gonadal steroids, including

dihydrotestosterone and testosterone for men. At the same time, in women, when histrelin is

continuously administered, it results in decreased LH and FSH levels. This is caused by the

down-regulation of the GnRH receptors, which is reversible within the pituitary gland, and also,

this is caused by pituitary gonadotropes desensitization. When patients are treated for more

extended periods with the use of histrelin, LH's response to GnRH is suppressed. This, in turn,

leads to decreased levels of LH down to pre-pubertal levels, especially within a treatment period

of 1 month. As a result of this, sex steroids, i.e., estrogen and testosterone concentrations,

decrease. During (CPP) Central Precocious Puberty treatment, it is essential to use histrelin

treatment since it prevents subsequent sexual body development for many patients. Besides, this

slows the linear velocity of body growth hence improving the chances of the patients attaining

the expected heights in adulthood. This is essential because it helps slow down the bones'
Side effects of different agents of GnRH analogues in Men and Women

abnormal fast development to ensure that both height and the children's growth rate are

reasonable. Also, it helps stop or reverses puberty early signs in children such as pubic hair and

breast growth in girls and the growth of pubic hair for boys.

Histrelin is mostly useful in the treatment of CPP in children, and also is essential in the

treatment of APC. In men, histrelin is used in the treatment of APC. Although it is not

considered to be a cure, it is believed that the different prostate cancer types depend on the male

testosterone hormone to grow and spread in the body. Histrelin helps to reduce testosterone

amounts produced by the body. This helps this slowdown or even completely stops the growth of

cancer cells in the body, hence relieving some prostate cancer symptoms such as patients having

difficulties during urination or pain urination.

There are various side effects associated with the use of histrelin treatment, such as mood swings,

irritation, and pain within the implant site, patients having severe headaches. For mean under prostate

cancer treatment using histrelin, they may have side effects such as hot flashes, tiredness, sweating at

night, ankle swelling, and experiencing constipation. During early puberty treatment in girls, the side

effects associated with histrelin include girls experiencing abnormal virginal bleeding and having

breast tenderness.

Leuprolide

Leuprolide is a GnRH analogue, and it is considered to functions as a GnRH receptor

super-agonist. After an initial spike in GnRH-mediated steroidal production, this includes

estradiol and testosterone. The prolonged use of leuprolide leads to a drop in the circulation of

steroid levels. This is in line with hormones produced through different ways of androgen-

deprivation therapy (ADT) (Hoda, 2007).

Side effects of different agents of GnRH analogues in Men and Women

Leuprolide is a synthetic 9-residue peptide analogue of GnRH. As compared to other

endogenous GnRH analogues, leuprolide has a single D-amino acid (D-leucyl) residue, and this

is important since it helps in increasing leuprolide half-life circulation from about 3 to 4 minutes

to about 3 hours. Leuprolide can bind to the GnRH receptor (GnRHR); hence this leads to

down-modulation in the levels of both sex steroid and gonadotropin hormones. When GnRHR

activation is prolonged, this leads to the downregulation of the levels of sex steroids. This

induces clinical efficacy with leuprolide in different conditions such as endometriosis, CPP, and

advanced prostate cancer (Hoda, 2007). Leuprolide is essential in treating APC, and also it is

applied in treating CPP in children under the puberty stage. Also, leuprolide is used in the initial

treatment of endometriosis combined with other oral therapies such as norethisterone.

There are various adverse effects related to the use of leuprolide inpatient treatment. For

women under the treatment of endometriosis, they are required to make careful considerations

because this treatment has various side effects. Increased estradiol levels might lead to symptoms

worsening, such as prolonged bleeding and pains (Wilson, 2007). When leuprolide is used for

long periods, it might lead to the loss of bone mineral density. Other adverse effects include loss

of vision, migraine, and different cardiovascular diseases for patients undergoing leuprolide and

norethisterone treatment. Also, for patients with depression symptoms before, the symptoms

might worsen when they are under leuprolide treatment. In men under leuprolide treatment for

prostate cancer, there might be some side effects that are caused by the testosterone level spikes

such as tumor flare together with other symptoms which include pain in the bones, obstruction of

the bladder, compression of the spinal cord and hematuria (Wilson, 2007). In addition to these

adverse effects, the patients are also at risk of developing other diseases such as diabetes

cardiovascular diseases that might be manifested through cardiac deaths and stroke.
Side effects of different agents of GnRH analogues in Men and Women

This study's objective was to determine the different effects of GnRH analogues and mainly try

to relate Degarelix antagonists with the other GnRH agonists by determining their side effects on

the patients. Despite the importance of the GnRH agonists and antagonists, various benefits and

impacts are associated with using the different GnRH analogue.

2: METHODS

Objectives
Side effects of different agents of GnRH analogues in Men and Women

This meta-analysis objective was to discover the adverse effects of using the GnRH analogue to

treat various diseases but accurately advanced cancer treatment in both men and women. This

meta-analysis systematically analyzed GnRH antagonists' different benefits: the Degarelix and

the GnRH agonists used in advanced prostate cancer treatment. The comparison of the benefits

and side effects was based on oncological, biochemical, and safety profiles of the GnRH

analogues.

Search Strategy

To find all the eligible randomized controlled trials (RCT), the online databases such as the

Google scholar, PubMed, Web Med, clinicaltrial.gov, Cochrane Library, and Drug bank were

used. The searched RCTs compared the different benefits and negative effects of using GnRH

analogues in APC treatment. To obtain the articles, this study used the following terminologies,

such as Degarelix, GnRH effects, Use of GnRH, GnRH agonists, GnRH antagonists, LH,n order

FSH. This search was updated from 1995 to July 2015.

Eligibility Criteria

The inclusion criteria used to get the data mostly focused on men and women belonging to all

age groups with historical treatments of advanced prostate cancer treated with Degarelix GnRH

antagonists and other GnRH agonists such as Triptorelin inside the clinical trials. The selected

studies were directly analyzing the use of Degarelix and the other GnRH agonists in the

treatment of APC for different people in the same population. Only the randomized phase III trial

studies were selected to make the comparison accurately. This included different original

articles, reviews, and various clinical trials that have been done on the effects of GnRH

analogues. The eligibility selection did not have any restrictions in terms of language or the
Side effects of different agents of GnRH analogues in Men and Women

years; however, this included only the trials that were done on humans. The unpublished data or

the articles that were published as abstracts were excluded because they did not have the correct

information that was required for this study.

Data collection and data extraction

The PRISMA process was followed to report different studies. The flow-chart below

shows the number of identifies studies, the articles, and reviews that were excluded from the

research, and the included studies at different stages. All the publications were reviewed to

ensure that they were meeting the relevance of the meta-analysis question. To get additional

relevant articles, the in-text citation from the main reports was also identified. Different

information was obtained from the reports, including the patient population, baseline parameters,

methodology data, trial design used in the articles, treatments used, and oncologic efficacy

assessments, analysis of quality of life, safety, and biochemical evaluations done. Figure 1 below

indicates the followed PRISMA when conducting the study of the articles.
Side effects of different agents of GnRH analogues in Men and Women

Figure 1: This figure shows the flow chart diagram with the number of papers identified,

included and excluded in the meta-analysis. It indicates the number of articles that were eligible

for the review and the number of studies used in this analysis.
Side effects of different agents of GnRH analogues in Men and Women

Table 1: Different Characteristics of the trials that were included in the analysis
Side effects of different agents of GnRH analogues in Men and Women

Quality Assessment

To determine the publications' bias, this study used the funnel plot in plotting the values

of log-transformation of the relative sensitivity against the different standard errors to ensure

graphical inspection. The various articles were then reviewed according to the QUADAS criteria

given in the review by (Moher, 2009). The bias risk in the identified publications was evaluated

based on the duration of the studies, trial design for the education, and the participant dropout

rates.

Data Analysis

In analyzing the data obtained from different studies, the statistical software Rev

Manager software was used to conduct the review with all the primary outcomes being

continuous data. The variations of the primary outcomes were compared between Degarelix's use

and the other GnRH agonist analogues for the different studies. For every included study, this

study compared degarelix and the other outcomes of GnRH agonists, where this either

considered the entire chosen population or only considered people that were in non-metastatic or

metastatic cases only when possible. These comparisons were conducted based on various

profiles. One of them is Prostate cancer-specific survival, a biochemical profile that was the

outcomes on gonadotropins, PSA and testosterone, and oncological profiles to determine the

overall survival rates and the safety and effects profile.

In synthesizing the results, both Random effects and Fixed-Effects analysis comparing the two

analogue methods were performed. When calculating the confidence intervals for the fixed
Side effects of different agents of GnRH analogues in Men and Women

effects analysis, there is always an assumption that in each study, the intervention's actual effect

is considered to be the same value, hence implying that there is no statistical heterogeneity. The

random effect model works under the assumption that effects underestimation for the various

studies is not identical.

All the data was put into the RevMan statistical software, which was used to generate the

different forest plots for all primary outcomes, hence comparing the different studies. This

analysis utilized the MantelHaensze fixed-effect model that uses the assumptions that all the

trials used during the analysis have a similar treatment effect and also any difference that might

have occurred; it was by chance. The P values of less than 0.05 showed that a particular group

was significant compared to the other group. This meta-analysis used both Chi 2 test and I2 test

statistical methods in the analysis of heterogeneity among the different included studies, and

from these methods, I2 values greater than 50% indicated significant variation.

This study performed a sub-analysis for the two defined groups, including the clinically

defined non-metastatic prostate cancer and clinically known metastatic Prostate. Various GnRH

agonists were used from the included articles, but this study considered the treatments as

homogeneous groups related to degarelix treatment. This study analyzed multiple cases treated

with anti-androgen for the flare-up duration or treated concerning GnRH agonists for all periods.
Side effects of different agents of GnRH analogues in Men and Women

3: RESULTS

After eliminating all the articles and reviews based on the exclusion criteria, only nine

publications were found to be more relevant to this meta-analysis. There were five clinical trials

in the articles that described the tests, and they were found to be eligible; hence they were

included in this meta-analysis. Data from the trial done by Shore (2014) was obtained from

clinicaltrial.gov, and this did not have any extensive publications. The sample size of the prostate

cancer cases ranged between 40 and 848 as shown in table 1 where the methodology, the

treatments are done on the patients, the patient population, biochemical assessments done, the

baseline parameters that were used, safety, oncologic efficacy assessments that were done and

the analysis on quality of life are highlighted in the table. For all studies included in this meta-

analysis, the follow you duration was different; however, there were no trials that exceeded 364

days.

Some data from extensions of trials done in a trial by (Crawford, 2011), (Crawford et al.,

2014) and (Shore(B), 2014) were not included in the analysis because they had a crossover with

the main trials since they were extensions of the main trials, they did not have any data.

This review and meta-analysis had 1719 participants, both men, and women, where 1061

participants received advanced prostate cancer treatment. In 4 trials, there was the stratification

of different cases in non-metastatic and metastatic prostate cancer where there were 720 non-

metastatic and 151 metastatic cases.

In the use of GnRH agonists, one trial (Klotz et al.., 2008), which had 2001 cases

administered leuprolide to the patients with a dose of 7.5mg per month. In the other three trials
Side effects of different agents of GnRH analogues in Men and Women

( Anderson et al., 2013), ( Mason et al., 2013) and (Axcrona et al., 2012) had 174 cases that

administered 3.6mg of Goserelin per month. Another trial (Shore(A), 2014) had 283 cases where

Goserelin was administered in 10.8mg every three months.

In four trials with 496 cases, Degarelix that is a GnRH antagonist was administered with a

dosage of 240mg for the first one month, then the other months, a dose of 80mg/month was

administered. In one trial (Shore(A), 2014), with 565 cases, the dosage was given 480mg every

three months. In another trial (Klotz et al., 2008) with 202 cases and other comparison groups

where degarelix with a dose of 160 mg /month was administered.

Biochemical profile

All trials with 1719 cases were used in evaluating the biochemical profile where it was

the primary endpoint for two trials[ CITATION Sho142 \l 1033 ] and (Klotz et al.,

2008).Regarding testosterone, gonadotropin, and PSA variations in their levels, the data as

evaluated. All the trials in the studies did not exceed 364 days, but they had different time

durations. Both Degarelix and GnRH agonists maintained the suppression of testosterone and

estrogen to a level of 0.5ng/ml between the 28th and the last day, i.e., 364th day. The levels of

testosterone and estrogen were maintained for all follow-ups with 98% with Degarelix, and with

GnRH agonists, it was 96% for all cases. This had a P-value of 0.64. Between the 1 st and 28th

day, the levels of castration testosterone had a high percentage of 97% for treatment done with

degarelix, while treatment done with GnRH agonists had a 45% level with P-value as 0.02. The

meta-analysis on testosterone data was difficult since the trials were taken to be testosterone

heterogeneous; hence they could not be compared.

Side effects of different agents of GnRH analogues in Men and Women

In four trials (Axcrona et al., 2012), ( Mason et al., 2013), (Klotz al., 2008) and (Shore(A), 2014)

it was possible to carry out the analysis where from 1 st day to the 28th day, the levels of PSA had

a decline by 78% in the degarelix and in the GnRH agonists it was 71%.

Figure 2: Forest plot showing PSA variations for both Degarelix and GnRH agonists for the four

studies. For each study, the plots show a P=0.010 with a 76% heterogeneity for all the groups

having 95% confidence intervals. From the forest plot, the blue boxes indicate the weight of the

studies, which resembles the size of the research. The horizontal line in the forest plot indicates

the 95% confidence interval that was used. In contrast, the vertical line represents the line of no

effect as it used to show whether the outcome is significant or not significant. The black diamond

box in the forest plot gave the estimate when all the four studies were combined by plotting their

average. The results from this forest plot indicate that the PSA reduction at the 28 th day between

the two groups was statistically insignificant, as shown by the high heterogeneity.

From the biochemical profile done, it was possible to identify that all treatments

maintained the testosterone for the castration levels up to the last day where degarelix managed

to produce a higher percentage in the castration levels as compared to the GnRH agonist hence

this indicates that there was no difference in the variations of PSA level for both groups that

were used in the treatment.

Side effects of different agents of GnRH analogues in Men and Women

Oncological Profile

Only one trial (Klotz et al., 2008) with 408 cases was used in the evaluation of the

oncological profile, and these were considered not to be the primary endpoints of the study. It

was difficult to carry out a meta-analysis on the oncological profile since it only one trial that

had the data; hence, the results were put in a table, as shown in the figure below.

Figure 3: Oncological Results

In particular, the data was evaluated based on the progression of PSA free survival and

overall survival. This trial (Klotz et al., 2008) had not analyzed any data related to Prostate

cancer-specific survival. Also, there was no specific analysis of free survival within the 364 days

follow up. This trial's outcome indicates that the overall survival was significant for patients

under degarelix with 97.4% compared to patients under GnRH agonists, which were 95.1%.

From this study, there were more deaths of patients under the GnRH agonist treatment, where

there were nine death cases compared to patients under degarelix antagonists, which were five

death cases. However, for both groups within 364 days, the overall causes of prostate cancer and
Side effects of different agents of GnRH analogues in Men and Women

death causes appeared to be lower for both patients under GnRH agonists and degarelix groups

hence reducing the significance of evaluating the overall survival.

The outcomes from this trial suggest that in patients that are under GnRH agonists. PSA

progressions were more frequent as compared to patients under degarelix treatment. This means

that there are higher chances of patients under degarelix to arrive at 12 months with no signs of

PSA progression than patients under GnRH agonists, as shown in the figure above.

Safety and effects profile

All the five trials with a total of 1719 cases were used in the analysis of the safety profile,

although the follow-up duration was not similar for all studies, they did not go beyond 364 days.

As shown in figure 4 below, 61% of adverse events were reported in patients under degarelix

treatment, while the patients under GnRH agonists reported 58% adverse events.

Figure 4: Forest plot indicating the adverse events in patients compared to patients under GnRH

agonist and degarelix treatments. The forest plot indicates heterogeneity of 64% and a

confidence interval of 95% with P=0.003. From the forest plot, the blue boxes indicate the

weight of all studies, which indicates the size of the study. The horizontal line in the forest plot
Side effects of different agents of GnRH analogues in Men and Women

indicates the 95% confidence interval that was used. In contrast, the vertical line represents the

line of no effect as it shows whether the outcome is significant or not significant. The black

diamond box in the forest plot gave the estimate when all the four studies were combined by

plotting their average.

For patients receiving both Degarelix and GnRH agonist treatment, the dropout rates

caused by the adverse events of the treatments were found to be lower. As shown in the figure

below, the heterogeneity of 0% shows that this was statistically significant with the P> 1.Patients

under degarelix had a 5% dropout. In contrast, patients under GnRH agonists showed a 5 % drop

out of the study.

Figure 5: This forest plot shows the dropout of the patents due to adverse events associated with

treatment. It compares patients under degarelix and GnRH agonist treatments. The forest plot

uses a 95% confidence interval, with 1061 total participants. The p-value is 0.31, which is

greater than 1, with 0% heterogeneity. From the forest plot, the blue boxes indicate the weights

of all studies, which indicate the size of the studies. The horizontal line in the forest plot

indicates the 95% confidence interval that was used.

In contrast, the vertical line represents the line of no effect as it shows whether the outcome is

significant or not significant. The black diamond box in the forest plot gave the estimate when all
Side effects of different agents of GnRH analogues in Men and Women

the four studies were combined by plotting their average. The outcome represented in this forest

plot indicates that the outcome of the comparison is insignificant.

From the analysis, the common adverse events that were reported in the patients were flushing,

where the patients had the side effects of hot flushes during the treatments. There were 29% of

the reported cases for patients under Degarelix treatment, while patients under GnRH agonists

reported 27% of the cases. This shows that both GnRH agonists and antagonists have effects on

the patients.

Figure 6: This forest plot compares GnRH agonists and Degarelix by defining their advance

effects of flushing adverse effects associated with the treatments. This forest plot indicates a 0%

heterogeneity, implying statistical significance in the comparison, as shown in graph with odds

Ratio. This forest plot has a p-value of 0.62 for the comparison. The advanced effects of hot

flushes are associated with treatment using GnRH analogues.

Side effects of different agents of GnRH analogues in Men and Women

Figure 7: Forest plot showing the comparison between the injection effects of the use of

degarelix and GnRH agonist in treatments. This forest plot indicates that the differences are

significant, and there are adverse effects of using the two treatments in all studies, as shown by a

high percentage (93%) of heterogeneity. The P-value is less than 1 (p=0.00001) hence showing

the significance of these effects.

Figure 8: Forest plot showing the adverse effects associated with the use of both Degarelix and

GnRH treatments on cardiovascular effects. There is significance in the effects associated with

the use of GnRH analogues on the patients.

The figure shown below indicates the different incidence associated with the use of

Degarelix and GnRH agonists in treatments where they cause various advance effects in both

men and women.

Side effects of different agents of GnRH analogues in Men and Women

Figure 9: Adverse effects of GnRH analogues as it is given in the trials. This figure indicates the

different common adverse effects of the use of both Degarelix and GnRH agonists when treating

patients. As shown in the figure, there are high adverse effects of injects associated with the use

of GnRH agonists as compared to use of Degarelix antagonist; also both treatments report high

cases of hot flushes where there about 29000 cases of hot flushes reported due to use of GnRH

agonist treatment and 2716 cases reported on the use of degarelix treatment in both men and

women. The two treatments do not have many adverse effects on male erectile dysfunction since

there are few reported cases.

Side effects of different agents of GnRH analogues in Men and Women

4: DISCUSSION

GnRH analogues have been widely used in treatments where they have been the ADT

standard of care for many years. However, various drawbacks are associated with the use of

GnRH agonists and antagonists in treatment due to how they act on the patient’s body. The use

of GnRH agonists delays the castration level development after the initial surge of testosterone.

This meta-analysis was limited to analyze the different effects associated with the use of GnRH

analogues and particularly comparing the various effects of Degarelix antagonist and GnRH

agonists such as leuprolide used in advanced prostate cancer treatment because many

international guidelines and clinical trials are mostly referred to degarelix for better analysis. The

comparison in this meta-analysis was made in terms of oncological, biochemical, and safety

profiles. The selected trials were related to both men and women, but the heterogeneity observed

in the analysis was because the trials had different characteristics in terms of the population,

GnRH analogues used, and the follow-up periods for the trials.

From the meta-analysis analysis, it was possible to identify important information

obtained from the RCTs, as shown in both treatment methods' biochemical profile for two

clinical trials. This was the endpoint. All trials used in the analysis indicate that both Degarelix

and GnRH agonists maintain testosterone suppression levels of castration up to the 364 th day.

However, this analysis only analyzed the first 364 days of treatment.

From this analysis, it was possible to identify that the use of GnRH antagonist

(Degarelix ) can help in slowing the PSA progression which in turn helps in improving the

patient health which is related to the quality of life where this was also suggested in the research
Side effects of different agents of GnRH analogues in Men and Women

done by (Lee, 2015). However, there are no significant effects on the quality of life caused by

these treatments, especially when Degarelix's use was compared with the use of leuprolide.

Some studies such as ( Mason et al. (2013) suggested that degarelix has more advantages

than the GnRH agonists when used in radiotherapy treatment; however, there was not enough

data to support the hypothesis. From this meta-analysis, it was possible to show that there could

be more advantages when the prostate volume is reduced compared to radiotherapy treatments.

In the analysis of safety and effects profiles, this meta-analysis indicates a good profile

for both GnRH agonists and Degarelix's uses since they show lower dropout rates due to adverse

events. Only injection site reactions from the analysis show a significant difference between the

two. The rate of reactions caused by this injection was higher when degarelix was used, as shown

in P<0.000001 and 95% confidence interval.

Various analysis (Smith, 2011) and (Smith, 2010) in their review, they suggest different

cardiovascular effects profile with the use of degarelix. However, the meta-analysis results show

that the cardiovascular effects resulting from treatment such as cardiac failure in patients, atrial

fibrillation, and angina pectoris were only reported in three trials with fewer than 12 months. The

use of GnRH agonists had a higher percentage of 3% in causing cardiovascular effects, while

Degarelix's use had 1% effects.

Side effects of different agents of GnRH analogues in Men and Women

Limitations

In this meta-analysis, there were various limitations, including heterogeneity with the

different studies included in the analysis. The studies did not have the same follow up periods;

however, all studies were limited to the 364 days of follow up. Another limitation was that the

evaluation of the oncological results only used one trial (Klotz et al., 2008), which was not the

primary endpoint. The data obtained from the trial (Shore(A), 2014) had not been fully

published; hence, the oncological results were unavailable from clinical trial.gov.

Future research

In the future, the meta-analysis should try to consider using studies that have similar

follow-up periods to effectively determine the adverse effects associated with the use of GnRH

analogues. Also, in future research, the researchers can use a certain group of people from the

population rather than using studies done only in men and women. This will be important

because different groups respond differently to different types of treatment.

Side effects of different agents of GnRH analogues in Men and Women

5: CONCLUSIONS

From the analysis, it was possible to determine the various side effects associated with

the use of GnRH analogues, especially the GnRH agonists and the antagonist Degarelix. From

the analysis, it was possible to find out that the use of both agonists and antagonists maintains the

levels of testosterone in men and estrogen in women when its use is limited within one year. The

analysis found that some side effects such as erectile dysfunction, hot flushes, and cardiovascular

effects were prone in the patients put under the GnRH analogue treatments. These side effects

indicate the drawbacks of using the GnRH analogue in the treatment of advanced prostate cancer

in both men and women. The main side effects associated with the use of degarelix antagonist

was found to be site injection reactions. This antagonist also had lower cardiovascular effects on

the patients. Therefore it was possible to conclude that there are various side effects associated

with the use of GnRH analogues treatment methods, but this can always be counter checked with

other treatment methods because some of the GnRH analogues may not cause severe adverse

effects to the patients. This meta-analysis recommends that it is important for more clinical trials

to be conducted to understand whether all the GnRH analogues have severe effects on the

patients because some of the GnRH analogues are more effective in the treatments.

X
Side effects of different agents of GnRH analogues in Men and Women

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