GnRH

In female sheep and goats, exposure to males can be used to induce ovulation and thus control and synchronise fertility. This
‘male effect’ offers simple, cost-effective, and hormone-free management of reproduction in flocks and herds but, despite decades of
research, significant gaps in our knowledge impede commercial application. Many of these gaps can be traced back to misconceptions in the early documentation of the male effect, and others are the result of uncontrolled factors in experimental design. Consequently, it is
often difficult to draw conclusions from past research, to further our understanding of the phenomenon, and to make recommendations
for industry application. Here, we describe 2 aspects of the male stimulus used to elicit the male effect that are often uncontrolled – the
novelty of the stimulus males and factors that contribute to variability in the potency of the male stimulus. We discuss the physiology
that underpins novelty, including the individual specificity of the socio-sexual signals emitted by the male, and the concomitant ability
of females to distinguish among individual males and remember them. Importantly, an understanding of the issue of novelty can make
it easier to use the male effect in commercial practice. We also discuss difficulties in interpretation caused by variation in endpoints of
the male effect (from neuroendocrine reaction to birth). We conclude that more rigour is needed in the control and reporting of male
novelty, in pre-experimentation separation of the sexes, and in extrapolation from detection of early responses to the male stimulus to
reproductive outcomes.

Benign prostatic hyperplasia (BPH) is a pathologic condition of the prostate described as a substantial increase in its number of epithelial and stromal cells. BPH may significantly reduce the quality of life due to the initiation of bladder outlet obstruction and lower urinary tract syndromes. Current medical therapies mostly consist of inhibitors of 5α-reductase or α1-adrenergic blockers; their efficacy is often insufficient. Antagonistic analogs of neuropeptide hormones are novel candidates for the management of BPH. At first, antagonists of luteinizing hormone-releasing hormone (LHRH) have been introduced to the therapy aimed to reduce serum testosterone levels.  However, they have also been found to produce an inhibitory activity on local LHRH receptors in the prostate as well as impotence and other related side effects. Since then, several preclinical and clinical studies reported the favorable effects
of LHRH antagonists in BPH. In contrast, antagonists of growth hormone-releasing hormone (GHRH) and gastrin-releasing peptide (GRP) have been tested only in preclinical settings and produce significant reduction in prostate size in experimental models of BPH. They act at least in part, by blocking the action of respective ligands produced locally on prostates through their respective receptors in the prostate, and by inhibition
of autocrine insulin-like growth factors-Ⅰ/Ⅱ and epidermal growth factor production. GHRH and LHRH antagonists were also tested in combination resulting in a cumulative effect that was greater than that of each alone. This article will review the numerous studies that demonstrate the beneficial effects of antagonistic analogs of LHRH, GHRH and GRP in BPH, as well as
suggesting a potential role for somatostatin analogs in experimental therapies.

Selection for increased growth rate and yield over the past 50 + years has dramatically altered the 'physiology' of the modern broiler breeder chicken. One consequence of the dramatic improvements in growth rate has been a tremendous reduction in the broiler breeder's reproductive capacity- numbers of eggs produced and fertility. This period of genetic selection has also resulted in a reduction in the quality and numbers of viable sperm produced and in the overall duration of fertility in broiler breeders. Other consequences of this selection include the requirement for quantitative feed restriction of breeders (both male and female) and a significant reduction in the reproductive 'life-expectancy' of breeders. In commercial flocks, it is very common for fertility to begin to decline immediately following 'peak' egg production. As a result, producers are frequently bringing new, younger, males into their flock, a process known as spiking, to rescue fertility. Based on our observations, we propose that a primary cause for the decline in fertility observed in post-peak production flocks is the loss of the robust pattern of episodic release of FSH and LH by the pituitary. Specific radioimmunoassays for chicken and/or other avian follicle stimulating hormone (FSH) have been developed. Despite this, and the sequencing of chicken FSH' sub-unit cDNA and gene (Yang et al. [GenBank Accession number AF467082]), there is a general paucity of information regarding FSH synthesis and release in birds, including chickens. While GnRH has a clear and demonstrable role in the regulation of FSH synthesis and secretion in mammals, the role of GnRH, if any, in regulating FSH in the fowl is less well defined.

Management of castration-resistant prostate cancer (CRPC) is challenging due to lack of efficacious therapy. Luteinizing hormone-releasing hormone (LHRH) analogs appear to act directly on cells based on the LHRH receptors on human prostate adenocarcinoma cells. We explored anticancer activity of a cytotoxic analog of LHRH, AEZS-108, consisting of LHRH agonist linked to doxorubicin. Nude mice bearing DU-145 tumors were used to compare antitumor effects of AEZS-108 with its individual constituents or their unconjugated combination. The tumor growth inhibition of conjugate was greatest among treatment groups (90.5% inhibition vs. 41% by [D-Lys(6)]LHRH+DOX). The presence of LHRH receptors on DU-145 cells was confirmed by immunocytochemistry. In vitro, AEZS-108 significantly inhibited cell proliferation (61.2% inhibition) and elevated apoptosis rates (by 46%). By the detection of the inherent doxorubicin fluorescence, unconjugated doxorubicin was seen in the nucleus; the conjugate was perinuclear and at cell membrane. Autophagy, visualized by GFP-tagged p62 reporter, was increased by AEZS-108 (7.9-fold vs. 5.3-fold by DOX+[D-Lys(6)]LHRH. AEZS-108 more effectively increased reactive oxygen species (ROS, 2-fold vs. 1.4-fold by DOX+[D-Lys(6)]LHRH) and levels of the apoptotic regulator p21 in vivo and in vitro. We demonstrate robust inhibitory effects of the targeted cytotoxic LHRH analog, AEZS-108, on LHRHR positive castration-resistant prostate cancer cells.

The introduction of new cytotoxic substances as well as agents that target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling has improved clinical outcome of patients with metastatic colorectal cancer (mCRC). In this review we summarize the most relevant clinical data on VEGF and EGFR targeting regimens in mCRC. The effects of available treatment strategies for mCRC are often temporary, with resistance and disease progression developing in most patients. Thus, new treatment strategies are urgently needed. Some GI peptides including gastrin and gastrin releasing peptide, certain growth factors such as insulin-like growth factor-I and II and neuropeptides such as growth hormone releasing hormone (GHRH) are implicated in the growth of CRC. Experimental investigations in CRC with antagonistic analogs of bombesin/gastrin-releasing peptide, GHRH, and with cytotoxic peptides that can be targeted to peptide receptors on tumors, are summarized in the second part of the review.

Abstract: Androgen deprivation therapy remains the mainstay of medical treatment for advanced prostate cancer. Commonly, this is achieved with medical androgen deprivation rather than surgical intervention as the permanence and psychological effects of the latter are unacceptable for most patients. Degarelix is a third generation antagonist of luteinizing hormone-releasing hormone (LHRH, also termed gonadotropin-releasing hormone) for the first-line treatment of androgen-dependent advanced prostate cancer. Degarelix acts directly on the pituitary receptors for LHRH, blocking the action of endogenous LHRH. The use of degarelix eliminates the initial undesirable surge in gonadotropin and testosterone levels, which is produced by agonists of LHRH. Degarelix is the most comprehensively studied and widely available LHRH antagonist worldwide. Clinical trials have demonstrated that degarelix has a long-term efficacy similar to the LHRH agonist leuprolide in achieving testosterone suppression in patients with prostate cancer. Degarelix, however, produces a faster suppression of testosterone and prostate-specific antigen (PSA), with no testosterone surges or microsurges, and thus prevents the risk of clinical flare in advanced disease. Recent clinical trials demonstrated that treatment with degarelix results in improved disease control when compared with an LHRH agonist in terms of superior PSA progression-free survival, suggesting that degarelix likely delays progression to castration-resistant disease and has a more significant impact on bone serum alkaline phosphatase and follicle-stimulating hormone. Degarelix is usually well tolerated, with limited toxicity and no evidence of systemic allergic reactions in clinical studies. Degarelix thus represents an important addition to the hormonal armamentarium for therapy of advanced androgen-dependent prostate cancer.

Novel drugs are required for the treatment of
CRPC. The best option may not be the agents
that target androgen receptors or compounds
which inhibit enzymes involved in androgen
biosynthesis. This is because the androgen
deprivation created by these compounds
can be overcome by mutations in androgen
receptors, the appearance of splice variants
of these receptors or alternate biochemical
pathways.
The use of currently available cytotoxic
analogs of LHRH, or somatostatin that can
be targeted to prostate cancers may lead to
an improvement in the treatment of CRPC
and an increase in the survival rate. A new
modality based on GHRH antagonists also
appears to be useful for the treatment of
metastatic CRPC.