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Mechanism of action of gonadotropin-releasing hormone agonists.9 Adapted from Conn and Crowley, used with permission. Abbreviations: GnRH, gonadotropin-releasing hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone.
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Androgen deprivation therapy (ADT) is the most effective systemic treatment for prostate cancer. ADT has been shown to have a high rate of response and to improve overall survival in patients with metastatic prostate cancer. In addition, multiple studies have shown that adding ADT to external beam radiation therapy leads to improvement in cure rate...
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We aimed to evaluate the change in bone mineral density (BMD) in patients with prostate cancer (PCa) receiving androgen deprivation therapy (ADT) compared to those with PCa or other urologic conditions not receiving ADT. Literature searches were conducted throughout October 2018. The eligibility of each study was assessed according to Preferred Rep...
Background: Osteoporosis is a common problem in postmenoausal women. There is limited data about the physiological importance of endogenous testosterone on bone mineral density (BMD) in older women is poorly understood.
Aim: The aim of this study was to evaluate association of endogeneous testosterone with BMD and BMI.
Materials-methods: This cross...
Background:
Luteinising hormone-releasing hormone agonists (LHRHa), used as androgen deprivation therapy (ADT) in prostate cancer (PCa) management, reduce serum oestradiol as well as testosterone, causing bone mineral density (BMD) loss. Transdermal oestradiol is a potential alternative to LHRHa.
Objective:
To compare BMD change in men receiving...
OBJECTIVE: Compare levels of androgens and bone mineral density (BMD) of ovariectomized (OVX) and non-ovariectomized (NOVX) postmenopausal women. Forty women, 20 OVX and 20 NOVX, (53.9 ± 4 years) were selected. METHODS: Total testosterone (TT), free testosterone (FT), androstenedione (AN), dehidroepiandrostenedione (DHEA) and its sulfate (DHEA-S) w...
Citations
... Since prostate cancer growth and progression are usually androgen-dependent, ADT with gonadotropin-releasing hormone (GnRH) receptor agonists or antagonists (including luteinizing hormone-releasing hormone [LHRH] analogues) is a staple for patients with advanced prostate cancer [4]. While effectively suppressing testosterone, and thereby prostate cancer progression, these drugs are often associated with hormonal symptoms such as hot flashes, loss of libido, and erectile dysfunction, as well as other negative impacts on patients' daily lives [5,6]. ...
This qualitative research study was conducted to develop a novel, comprehensive, patient-reported outcome measure (PRO), the “Symptoms and Impacts of Androgen Deprivation Therapy (ADT) for Prostate Cancer” (SIADT-PC), assessing hormonal therapy-related symptoms and their impacts on men with advanced prostate cancer.
Concept elicitation (CE) interviews were conducted among adult men with prostate cancer to evaluate their experiences with ADT. Based on key symptom and impact concepts mentioned, an initial PRO measure was developed. The draft measure was further assessed in cognitive debriefing (CD) interviews with men with prostate cancer, in which participants reviewed items, response options, and recall periods. Initial item-based psychometric analyses were conducted using interview data. The draft questionnaire was revised on the basis of participant feedback, quantitative psychometric results, and consultation with clinical experts.
A total of 21 participants were interviewed (CE concept elicitation, n = 12; CD cognitive debriefing, n = 17; n = 8 completed both). Mean participant age (SD) was 59.7 (8.7) years and 76.2% were white. The de novo SIADT-PC measure consists of 27 items: 11 symptoms (e.g., fatigue, hot flashes, and erectile dysfunction), 2 long-term symptoms (e.g., weight gain), 10 impacts (e.g., impacts on physical activities and relationships), and 4 related to mode of administration (i.e., injection-site reactions). Items were assessed with a 5-point verbal rating scale, with answer choices that capture frequency or severity.
Once fully validated, this de novo measure may be used in clinical studies and clinical practice to assess hormone therapy-related symptoms and impacts, enabling physicians to identify timely and appropriate interventions.
... Treatment for prostate cancer often relies on either radiation therapy or a surgical procedure called a prostatectomy, both of which attempt to eliminate any remaining cancer cells that haven't already spread or metastasized (Sekhoacha et al. 2022). However, many patients are unable to be completely cured by this treatment, which is subsequently followed by cancer recurrence and/or metastasis (Choi and Lee 2011). The vast majority of prostate cancer growth is androgen-dependent. ...
... The vast majority of prostate cancer growth is androgen-dependent. The most effective therapeutic intervention for the treatment of androgen-dependent prostate cancer (ADPC) is androgen deprivation therapy (ADT) in the form of surgery or gonadotropin-releasing hormone (GnRH) analog treatment (Choi and Lee 2011). However, within 13 to 24 months following therapy, most of these patients become androgen-independent, progress, metastasize, and resist ADT while also experiencing rising prostatespecific antigen (PSA) levels. ...
Androgen receptor (AR) is known to play a crucial role in the development and progression of prostate cancer, and compounds that inhibit its activity are regarded as promising for the development of drugs to treat the disease. This study aimed to investigate the AR-inhibiting potential of Citrullus lanatus fruit compounds for prostate cancer drug development. Following HPLC identification, the binding energies, molecular interactions, and pharmacological potentials of the compounds against AR were elucidated using in silico techniques such as, molecular docking, induced-fit docking, molecular dynamics simulation, and ADMET prediction. Some of the compounds found to be present in Citrullus lanatus fruit included flavonoids such as proanthocyanin, naringin, flavan 3 ol, flavonones, naringenin, epicatechin, citrulline, and catechin. Naringenin exhibited the highest docking score in the molecular docking analysis, followed by resveratrol, ribalinidine, and epicatechin. These compounds share a common AR binding site with the standard ligand, dihydrotestosterone (DHT). Some of the compounds showed favorable ADMET profiles, while others showed at least one toxicity potential. The induced-fit docking of naringenin with AR yielded a higher docking score than the initial score obtained from standard docking while preserving stable molecular contacts with the interacting amino acids. Consistent hydrogen bond interactions of naringenin with PHE 764, ASN 705, and THR 877 of AR, including a persistent pi-pi stacking contact with PHE 764, were observed from the molecular dynamic simulation. The Citrullus lanatus compounds, particularly naringenin, may therefore be considered for further research towards the development of drugs for prostate cancer therapy.
... Although there is a plethora of data available on the matter at hand, there still exist several obstacles that limit access to fertility preservation techniques and mechanisms [14,17], while it is also notable that there are very limited data on the number of patients that are willing to adopt any of these preservation techniques. The lack of this information also affects the public health sector and the health organization system to cater to both fertility and oncology units. ...
... The use of Gonadotropin-releasing hormone agonists aims to lower both gonadotropins and sex hormone levels. They are commonly used to lower sex hormone levels in the treatment of hormone-sensitive cancers like breast and prostate cancers [17]. The mechanism by which ovarian suppression during chemotherapy protects ovarian function is not clear. ...
Introduction: Breast cancer affects almost 1.5 million women worldwide below the age of 45 years each year. Many of these women will be advised to undergo adjuvant chemotherapy to minimize the risk of death or recurrence of the tumor. For these patients, chemotherapy is a known cause of infertility, as it can damage primordial follicles, which can lead to early menopause or premature ovarian insufficiency. This systematic review aims to synthesize the current evidence of the most suitable treatments for fertility preservation. Methodology: This review was performed following the PRISMA guidelines. The authors conducted an extensive search from the last 15 years. Relevant studies were pursued in PubMed, Embase, and the Cochrane Library up until 31 July 2023. A total of seven eligible studies were identified. Results: From the reviewed literature, ovarian suppression with gonadotropin-releasing hormone agonists showed promising results in preserving fertility for breast cancer patients undergoing chemotherapy. Additionally, oocyte and embryo cryopreservation demonstrated successful outcomes, with embryo cryopreservation being the most effective option. Notably, the slow-freezing and vitrification methods were both effective in preserving embryos, with vitrification showing superior results in clinical-assisted reproductive technologies. Ovarian tissue cryopreservation emerged as a viable option for prepubertal girls and those unable to undergo conventional ovarian stimulation. The potential of in vitro maturation (IVM) as an alternative method presents a promising avenue for future fertility preservation research. Discussion: The most suitable treatments for fertility preservation in young patients is the temporary suppression with luteinizing hormone-releasing analogs, while the patient undergoes chemotherapy and cryopreservation. For cryopreservation, the physicians might deem it necessary to either cryopreserve ovarian tissue taken from the patient before any treatment or cryopreserve embryos/oocytes. Cryopreservation of oocytes and/or embryos is the most effective solution for fertility preservation in women of reproductive age, who have a sufficient ovarian reserve and are diagnosed with breast cancer, regardless of the histological type of the tumor. Because approximately 50% of young breast cancer patients are interested in becoming pregnant right after completion of therapy, the evolution and development of fertility preservation techniques promise to be very exciting.
... Apalutamide, darolutamide, or enzalutamide are recommended for non-metastatic CRPC with a high risk of disease progression. Abiraterone or enzalutamide or Docetaxel or cabazitaxel or denosumab are recommended for metastatic CRPC patients [142][143][144] (Fig. 5). ...
... Muscle atrophy, erectile dysfunction, insulin resistance and diabetes, increased fat mass, estrogen deficiency, and anemia are some of the side effects of ADT. The treatment strategies for localized prostate cancer seem to be effective for a short period, as a larger percentage of these patients are at high risk of developing AIPC and metastasis [142]. Moreover, the treatments for CRPC have a moderate anti-cancer effect and are not fully effective, as studies suggested that elevated androgen level is not the only cause for initial prostate cancer development [13,145]. ...
Cancer is the second leading cause of death worldwide, with prostate cancer, the second most commonly diagnosed cancer among men. Prostate cancer develops in the peripheral zone of the prostate gland, and the initial progression largely depends on androgens, the male reproductive hormone that regulates the growth and development of the prostate gland and testis. The currently available treatments for androgen dependent prostate cancer are, however, effective for a limited period, where the patients show disease relapse, and develop androgen-independent prostate cancer (AIPC). Studies have shown various intricate cellular processes such as, deregulation in multiple biochemical and signaling pathways, intra-tumoral androgen synthesis; AR over-expression and mutations and AR activation via alternative growth pathways are involved in progression of AIPC. The currently approved treatment strategies target a single cellular protein or pathway, where the cells slowly develop resistance and adapt to proliferate via other cellular pathways over a period of time. Therefore, an increased research aims to understand the efficacy of combination therapy, which targets multiple interlinked pathways responsible for acquisition of resistance and survival. The combination therapy is also shown to enhance efficacy as well as reduce toxicity of the drugs. Thus, the present review focuses on the signaling pathways involved in the progression of AIPC, comprising a heterogeneous population of cells and the advantages of combination therapy. Several clinical and pre-clinical studies on a variety of combination treatments have shown beneficial outcomes, yet further research is needed to understand the potential of combination therapy and its diverse strategies.
... Apalutamide, darolutamide, or enzalutamide are recommended for non-metastatic CRPC with a high risk of disease progression. Abiraterone or enzalutamide or Docetaxel or cabazitaxel or denosumab are recommended for metastatic CRPC patients [142][143][144] (Fig. 5). ...
... Muscle atrophy, erectile dysfunction, insulin resistance and diabetes, increased fat mass, estrogen deficiency, and anemia are some of the side effects of ADT. The treatment strategies for localized prostate cancer seem to be effective for a short period, as a larger percentage of these patients are at high risk of developing AIPC and metastasis [142]. Moreover, the treatments for CRPC have a moderate anti-cancer effect and are not fully effective, as studies suggested that elevated androgen level is not the only cause for initial prostate cancer development [13,145]. ...
Cancer is the second leading cause of death worldwide, with prostate cancer, the second most commonly diagnosed
cancer among men. Prostate cancer develops in the peripheral zone of the prostate gland, and the initial
progression largely depends on androgens, the male reproductive hormone that regulates the growth and development
of the prostate gland and testis. The currently available treatments for androgen dependent prostate
cancer are, however, effective for a limited period, where the patients show disease relapse, and develop androgen-
independent prostate cancer (AIPC). Studies have shown various intricate cellular processes such as,
deregulation in multiple biochemical and signaling pathways, intra-tumoral androgen synthesis; AR over-expression
and mutations and AR activation via alternative growth pathways are involved in progression of AIPC.
The currently approved treatment strategies target a single cellular protein or pathway, where the cells slowly
develop resistance and adapt to proliferate via other cellular pathways over a period of time. Therefore, an
increased research aims to understand the efficacy of combination therapy, which targets multiple interlinked
pathways responsible for acquisition of resistance and survival. The combination therapy is also shown to enhance
efficacy as well as reduce toxicity of the drugs. Thus, the present review focuses on the signaling pathways
involved in the progression of AIPC, comprising a heterogeneous population of cells and the advantages of
combination therapy. Several clinical and pre-clinical studies on a variety of combination treatments have shown
beneficial outcomes, yet further research is needed to understand the potential of combination therapy and its
diverse strategies.
... Based on our hypothesis, GnRHR pathways contribute to leiomyoma growth and NAV3 may mediate this process. In addition to uterine tumors, there is evidence suggesting that [17,[27][28][29][30][31][32][33][34][35][36]. For example, in ovarian cancer, there is an extensive presence (80%) of GnRH binding sites on ovarian cancer biopsy samples, supporting the involvement of GnRH signaling and a possible autocrine loop [35]. ...
... For example, in ovarian cancer, there is an extensive presence (80%) of GnRH binding sites on ovarian cancer biopsy samples, supporting the involvement of GnRH signaling and a possible autocrine loop [35]. GnRHR has also been identified in 80% of malignant prostate tumors, and hormone-responsive prostate cancers are successfully treated with GnRH-a [36]. NAV3 may also play a role in cell-cell matrix adhesion and in actin cytoskeleton tethering. ...
NAV 3 is a tumor suppressor of unknown function in leiomyomas. The objective of this study is to assess NAV3 expression and its potential role in human uterine leiomyomas. NAV3 protein expression was examined in patient leiomyoma and patient-matched myometrial tissue samples by Western blot and immunohistochemistry. NAV3 mRNA and protein expression was assessed in leuprolide acetate- and cetrorelix-treated cell line leiomyoma samples. RNAseq analysis of placebo-treated leiomyoma compared with myometrium demonstrated the presence of transcripts encoding for several neuronal proteins. For NAV3, RNA sequence analysis demonstrated decreased expression in leiomyoma as compared with myometrium (0.86 ± 0.03 fold). Presence of NAV3 mRNA was also decreased in leiomyoma surgical samples (0.43 fold ± 0.05, p = 0.026) compared with patient-matched myometrium. Confirmatory qRT-PCR results on immortalized leiomyoma and myometrial cell lines similarly demonstrated a decrease in expression of NAV3 in leiomyomas (0.28 ± 0.02, p = 0.00075). Immunohistochemical analysis demonstrated a significant decrease in NAV 3 protein in leiomyomas (H-score 154.7 ± 6.2) as compared with myometrium (H-score; 312.5 ± 14.7, p < 0.0001). Leuprolide acetate-treated leiomyoma cells demonstrated an increase in NAV 3 mRNA expression (1.53 ± 0.13, p < 0.0001). Similarly, Western blot analysis on leuprolide-treated leiomyoma cells showed a non-significant increase in NAV 3 protein expression (1.26 ± 0.09, p = 0.063). NAV 3, a tumor suppressor in numerous cancers, is decreased in leiomyoma cells and tissue compared with myometrium, and increased by GnRH analog treatment, suggesting that NAV3 may mediate steroid hormone-independent leiomyoma regulation by GnRH analogs.
... (p < 0.01) *p, #p < 0.05 compared with PBS VEGF-M2 exhibited a lower survival rate than mice treated by VEGF-M2-GnRH3-hinge-MVP, GnRH3-hinge-MVP, CAZ and even PBS, which preliminary speculated that protein vaccine VEGF-M2 reacts negatively against the body in the process of anti-tumor, and also its relevant mechanism needs further exploration. On the same line, most of tumor angiogenesis targeting therapy focused on the treatment of anti-VEGF [17,23,24], while recent reports showed that tumor angiogenesis were lowered by GnRH through inhibiting VEGF expression [18,25]. Furthermore, GnRH-A expressed a powerful intrinsic ability to act on anti-EGF/TGFa system and reduced cell division, which might be associated with the induction of apoptosis and inhibition of P13/PKB signaling pathways intracellular [26]. ...
GnRH and VEGF have been investigated as prostate carcinoma enhancers that support tumor spread and progression. Although both have documented roles in prostate carcinoma and many cancer types, the weak immunogenicity of these peptides has remained a major challenge for use in immunotherapy. Here, we describe a novel strategy to inhibit GnRH and VEGF production and assess the effect on the immune responses against these hormones using the RM-1 prostate cancer model. We designed a novel recombinant fusion protein which combined GnRH and VEGF as a vaccine against this tumor. The newly constructed fusion protein hVEGF121-M2-GnRH3-hinge-MVP contains the human vascular endothelial growth factor (hVEGF121) and three copies of GnRH in sequential linear alignment and T helper epitope MVP as an immunogenic vaccine. The effectiveness of the vaccine in eliciting an immune response and attenuating the prostate tumor growth was evaluated. Results showed that administration of a new vaccine effectively elicited humoral and cellular immune responses. We found that, a novel fusion protein, hVEGF121-M2-GnRH3-hinge-MVP, effectively inhibited growth of RM-1 prostate model and effectively promoted immune response. In conclusion, hVEGF121-M2-GnRH3-hinge-MVP is an effective dual mechanism tumor vaccine that limits RM-1 prostate growth. This vaccine may be a promising strategy for the treatment of hormone refractory prostate malignancies.
... By contrast, treatment with vancomycin or lamivudine (Figs. 5 and 6, respectively) produced metabolite profiles that matched only a small number of MoA patterns associated with toxicity, none being associated with liver toxicity. While vancomycin treatment has not been associated with anemia (as might be expected by porphyrin inhibiton), lamivudine treatment has been associated with bone mineral content (Tsekes et al., 2002), a side effect of gonadotropin-releasing hormone (GnRH) agonism (Choi and Lee, 2011). Atropine treatment did result in a metabolite profile that had matches to patterns of kidney and bone marrow toxicity, as well as liver toxicity and liver enzyme induction (Fig. 7), but liver enzyme induction is generally viewed as a compensatory and not adverse response. ...
While conventional parameters used to detect hepatotoxicity in drug safety assessment studies are generally informative, the need remains for parameters that can detect the potential for hepatotoxicity at lower doses and/or at earlier time points. Previous work has shown that metabolite profiling (metabonomics/metabolomics) can detect signals of potential hepatotoxicity in rats treated with doxorubicin at doses that do not elicit hepatotoxicity as monitored with conventional parameters. The current study extended this observation to the question of whether such signals could be detected in rats treated with compounds that can elicit hepatotoxicity in humans (i.e., drug-induced liver injury, DILI) but have not been reported to do so in rats. Nine compounds were selected on the basis of their known DILI potential, with six other compounds chosen as negative for DILI potential. A database of rat plasma metabolite profiles, MetaMap(®)Tox (developed by metanomics GmbH and BASF SE) was used for both metabolite profiles and mode of action (MoA) metabolite signatures for a number of known toxicities. Eight of the nine compounds with DILI potential elicited metabolite profiles that matched with MoA patterns of various rat liver toxicities, including cholestasis, oxidative stress, acetaminophen-type toxicity and peroxisome proliferation. By contrast, only one of the six non-DILI compounds showed a weak match with rat liver toxicity. These results suggest that metabolite profiling may indeed have promise to detect signals of hepatotoxicity in rats treated with compounds having DILI potential.
... Lupron is a LHRH agonist that while initially increases the amount of FSH and LH, eventually causes a prolonged decrease in the release of FSH and LH due to continuous stimulation of the anterior pituitary -thus preventing androgen synthesis (Xu et al, 2012). In addition to castration, the use of Lupron and other LHRH agonists has become one of the most common androgen deprivation (ADT) therapies used in the prevention and treatment of prostate cancer (Choi and Lee, 2011). Despite multiple side effects that have been associated with Lupron treatment, the most prevalent being hot flushes; different approaches involving LHRH are being studied (Choi and Lee, 2011). ...
... In addition to castration, the use of Lupron and other LHRH agonists has become one of the most common androgen deprivation (ADT) therapies used in the prevention and treatment of prostate cancer (Choi and Lee, 2011). Despite multiple side effects that have been associated with Lupron treatment, the most prevalent being hot flushes; different approaches involving LHRH are being studied (Choi and Lee, 2011). Additionally, combining other agents, like AR antagonists such as bicalutamide, alongside the administration of Lupron can prevent the harmful side effects of the initial increase in circulating androgen levels (Heidegger et al, 2013). ...
Prostate Cancer (PCa) is the second leading cause of cancer death in men. Current research findings suggest that the androgen receptor (AR) and its signaling pathway contribute significantly to the progression of metastatic PCa. The AR is a ligand activated transcription factor, where androgens such as testosterone (T) and dihydroxytestosterone (DHT) act as the activating ligands. However in many metastatic PCa, the AR functions promiscuously and is constitutively active through multiple mechanisms. Inhibition of enzymes that take part in androgen synthesis or synthesizing antiandrogens that can inhibit the AR are two popular methods of impeding the androgen receptor signaling axis; however, the inhibition of androgen-independent activated AR function has not yet been fully exploited. This article focuses on the development of emerging novel agents that act at different steps along the androgen-AR signaling pathway to help improve the poor prognosis of PCa patients. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
... The approach taken in the treatment of prostate cancer will depend on several factors, including the clinical presentation, Gleason score, and PSA (2). For patients with metastatic spread of prostate cancer, such as the patient in this case, the treatment of choice is androgen-deprivation therapy (ADT) (2,3). ...
... GnRH antagonists (degarelix) have only recently received attention in the literature. GnRH agonists can cause an early increase in testosterone levels which, in turn, can promote tumor spread and worsen symptoms (2). GnRH antagonists can be used before the GnRH agonist therapy to block testosterone increases (2,7). ...
... GnRH agonists can cause an early increase in testosterone levels which, in turn, can promote tumor spread and worsen symptoms (2). GnRH antagonists can be used before the GnRH agonist therapy to block testosterone increases (2,7). GnRH antagonists can also be used as an alternative approach to androgen deprivation by inhibiting gonadotrophin production, leading to a reduction in the synthesis of androgens in the testes (7). ...
The role of nuclear medicine diagnostic bone scanning is well established in prostate cancer. This case provides an insight into the specific role that bone scanning plays in monitoring response to hormone therapy and an example of significant global skeletal response. The case highlights the remarkable efficacy of timely hormone therapy in high-grade prostate cancer with widespread bony metastasis. In addition, the range of hormone therapy currently available for clinical application in the management of metastatic prostate cancer is detailed. Finally, the case represents an incidental diagnosis of prostate cancer after evaluation of nonspecific symptoms.
