促性腺激素释放激素拮抗剂在性激素依赖性疾病中的应用

促性腺激素释放激素(GnRH)是下丘脑分泌产生的神经激素,其通过下丘脑-垂体-性腺轴调节女性发育和生殖功能,同时还以自分泌和旁分泌的方式作用于垂体外组织。研究发现,GnRH及其受体在正常及异常生殖相关组织均有表达,包括子宫内膜异位症、子宫内膜癌和卵巢癌。GnRH拮抗剂在性激素依赖性疾病治疗中占有重要地位。GnRH拮抗剂类药物治疗子宫内膜异位症、不孕和肿瘤等妇科疾病是国外最新研究的热点之一。     

促性腺激素释放激素类似物化学合成研究进展

促性腺激素释放激素是由下丘脑分泌的一种肽类物质,主要作用于生殖系统.经过人工合成改性、置换或者去除部分氨基酸得到了药效更优的促性腺激素释放激素类似物.该类化合物依据对垂体促性腺激素释放激素受体的作用被分为激动剂及拮抗剂.目前被广泛用于前列腺癌的临床治疗.本文综述了上市的七种用于治疗前列腺癌的促性腺激素释放激素类似物的化...     

性腺领域相关热点问题几点讨论

人体内的内分泌调节是通过许多功能调节＂轴＂（axis）来实现的,性腺轴是由下丘脑、垂体和外周性腺共同构成的。下丘脑的促性腺激素释放激素（GnRH）调节垂体的促性腺激素黄体生成素（LH）和卵泡刺激素（FSH）的分泌。促性腺激素再对外周性腺,即它的靶器官发挥作用。睾丸为男性的外周性腺器官,可合成分泌睾酮、雌激素、抑制素、     

促性腺激素释放激素类似物对肿瘤细胞增殖的抑制效应

研究促性腺激素释放激素类似物（GnRH analogue,GnRHa）抑制肿瘤细胞增殖的效应将为治疗癌症提供新方法。1．促性腺激素释放激素受体（GnRH receptor,GnRH—R）在肿瘤组织上的分布：人类的许多恶性肿瘤都表达GnRH—R受体。2．GnRHa对肿瘤细胞增殖的抑制作用：GnRHa不仅能够抑制激素依赖忡肿瘤的大部分细胞系增殖,而日肩B够抑制非激素依赖性肿瘤的一些细胞系增殖。3．GnRHa抑制肿瘤细胞增殖的分子机制：GnRHa的生物效应是通过阻碍生长因子受体介导的促有丝分裂信号传导发挥生物效应。     

GnRH类似物在乳腺癌治疗中的应用和卵巢功能保护

促性腺激素释放激素（gonadotropin—releasing hormone,GnRH）类似物治疗绝经前乳腺癌具有疗效好、停药后卵巢功能可恢复的特点,已取代手术和放疗成为治疗绝经前乳腺癌的一种主要治疗手段,现主要介绍GnRH类似物在乳腺癌内分泌治疗中的应用及其卵巢功能保护作用。     

GnRHa在临床的应用

天然促性腺激素释放激素（GnRH）是下丘脑肽能神经元分泌的10肽激素，是通过垂体门脉系统，刺激垂体前叶细胞合成卵泡刺激激素（FSH）和黄体生成激素（LH）。通过改变GnRH第6位和第10位氨基酸得到GnRHa，其生物效应较天然GnRH提高50—100倍。首次给药初期，GnRHa具有短暂刺激FSH和LH升高及反跳作用，使卵巢性激素短暂升高。持续应用后，则垂体受体被全部占满和耗尽，对GnRHa不再敏感，即垂体GnRHa受体脱敏，使FSH和LH大幅下降，导致卵巢性激素明显下降至近似于绝经期或手术去势水平。因此GnRHa在治疗子宫肌瘤、子宫内膜异位症、乳腺癌及卵巢癌等激素相关性疾病中均起到了重要的作用。     

男性低促性腺激素性性腺功能减退的临床诊断及药物治疗

男性低促性腺激素性性腺功能减退症（HH）是由于先天或后天因素使下丘脑和/或垂体合成、转运和分泌促性腺激素释放激素（GnRH）和/或促性腺激素（LH和FSH）障碍,导致睾丸功能减退,引起的一系列临床症状。HH临床表现因发病的时间不同而有差异,青春期前发病表现为外生殖器发育异常或延迟,青春期后发病导致不育或性功能障碍。根据患者病史、体格检查、染色体核型分析、性激素水平测定、GnRH或LHRH兴奋试验、骨龄测定、下丘脑-垂体磁共振成像,必要时行LH脉冲分析等方法可进行诊断与鉴别诊断。早期诊断是HH治疗的关键。治疗的主要目的是维持睾丸功能、促进第二性征发育,改善生活质量,可能的情况下恢复和重建生育能力。根据不同需要可以选择睾酮制剂、促性腺激素以及GnRH的脉冲泵治疗等。     

性腺功能减退症治疗方式的选择

性腺功能减退症是指发生在下丘脑一垂体一靶腺一终端靶细胞的病变导致的性激素缺乏临床综合征,其可分为高促性腺激素型和低促性腺激素型。性腺功能减退症的治疗方案通常有三种选择性激素替代治疗、促性腺激素治疗和GnRH脉;中治疗。三种治疗方案各有适应证和优缺点．本文将针对三种方案进行阐述。     

促性腺激素释放激素类似物在妇科疾病治疗中的应用

促性腺激素释放激素类似物广泛用于妇科疾病治疗,掌握其作用特点和使用方法可取得较好的效果。本文简要介绍促性腺激素释放激素类似物在妇科疾病治疗中的应用。     

GnRH泵治疗低促性腺激素性性腺功能减退

对于低促性腺激素性性腺功能减退（HH）患者,GnRH脉冲泵治疗与传统的促性腺激素治疗均可促进性腺的发育、性激素合成以及生殖细胞的成熟。连续的脉冲式给予GnRH类似物,使得垂体产生接近正常的促性腺激素脉冲,从而诱导性腺的发育,合成性激素并促进生殖细胞成熟。多数男性患者需要治疗至少2年,以最大限度地增大睾丸体积并实现精子生成。这一治疗方案仅适用于垂体功能正常的患者。通常认为,治疗前的睾丸体积是影响HH患者预后的主要因素之一,治疗前睾丸体积较大（〉4ml）,具有一定程度青春期发育的患者治疗效果更好。对于罹患HH的女性患者,接受GnRH治疗可诱导青春期发育,并促使卵泡成熟、排卵和维持黄体功能。目前普遍认为皮下给药方式具有良好的治疗效果和耐受性,因此推荐皮下注射为长期治疗时首选的给药方式。但对于GnRH脉冲泵治疗与传统促性腺激素治疗疗效的比较,以及决定治疗预后的因素等问题,仍需要更多临床资料进一步阐明。     

Hypothalamo-pituitary-gonadal axis in control of female reproductive cycle

Gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus is pivotal to the regulation of reproductive physiology in vertebrates. The characteristic periodic secretion of gonadotropin releasing hormone (GnRH) from the medial basal hypothalamus (MBH), at the rate of one pulse an hour is essential for the maintenance of the menstrual cycle. These pulses are due to oscillations in the electrical activity of the GnRH pulse generator in the MBH. The GnRH pulse generator is under the influence of an assortment of interactions of multiple neural, hormonal and environmental inputs to the hypothalamus. Hence, a number of conditions such as stress, drug intake, exercise, sleep affect the activity of this pulse generator. Any deviation of normal frequency results in disruption of normal cycle. The cycle can become anovulatory in the hypothalamic lesions and can be restored by exogenous administration of pulsatile GnRH. Of late, studies have shown that pulse generator activity is also maintained by specific metabolic signals meant for energy homeostasis. Studies are in progress to work out cellular basis of GnRH pulse generator's rhythmic activation and role of Ca++ as second messenger for GnRH stimulated gonadotropin release. New concepts are emerging to find the existence of an FSH releasing factor, which independently regulates the activity of FSH.     

Therapeutic potential of GnRH antagonists in the treatment of precocious puberty

Pituitary-gonadal axis activation depends upon pulsatile hypothalamic gonadotropin-releasing hormone (GnRH) secretion. This phenomenon has led to clinical use of GnRH agonists in the treatment of central precocious puberty. GnRH analogues contain substitutions of the native decapeptide. Depending upon the substitutions, the analogues have GnRH agonistic or antagonistic properties. The pharmacokinetics of GnRH agonists, the established treatment of precocious puberty, includes an initial 'flare-up' of the pituitary-gonadal axis, followed by a reduced luteinising hormone secretion by desensitisation of pituitary GnRH receptors. Antagonistic GnRH analogues act by competitive binding to the pituitary GnRH receptors, thereby preventing the action of endogenous GnRH - theoretically offering a more direct and dose-dependent treatment alternative. The antagonist available today in Germany is a concomitant in assisted reproduction with only 1 - 3 days duration. However, long-acting depot preparations of other GnRH antagonists are in primate-testing phase. Our animal tests indicate strong potential for the development and testing of long-acting depot preparations of GnRH antagonists in treating precocious puberty.     

Therapeutic potential of GnRH antagonists in the treatment of precocious puberty

Pituitary-gonadal axis activation depends upon pulsatile hypothalamic gonadotropin-releasing hormone (GnRH) secretion. This phenomenon has led to clinical use of GnRH agonists in the treatment of central precocious puberty. GnRH analogues contain substitutions of the native decapeptide. Depending upon the substitutions, the analogues have GnRH agonistic or antagonistic properties. The pharmacokinetics of GnRH agonists, the established treatment of precocious puberty, includes an initial ‘flare-up’ of the pituitary-gonadal axis, followed by a reduced luteinising hormone secretion by desensitisation of pituitary GnRH receptors. Antagonistic GnRH analogues act by competitive binding to the pituitary GnRH receptors, thereby preventing the action of endogenous GnRH – theoretically offering a more direct and dose-dependent treatment alternative. The antagonist available today in Germany is a concomitant in assisted reproduction with only 1 – 3 days duration. However, long-acting depot preparations of other GnRH antagonists are in primate-testing phase. Our animal tests indicate strong potential for the development and testing of long-acting depot preparations of GnRH antagonists in treating precocious puberty.     

Altered regulation of pituitary gonadotropin-releasing hormone (GnRH) receptor number and pituitary responsiveness to GnRH in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated male rats

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) increases the potency of androgens as feedback inhibitors of luteinizing hormone (LH) secretion. Our objectives were to determine if this increase is due to pituitary or hypothalamic dysfunction (or both), and to investigate the mechanism by which TCDD produces this effect. Seven days after dosing, TCDD inhibited the compensatory increases in (i) pituitary gonadotropin-releasing hormone (GnRH) receptor number, (ii) LH secretory responsiveness of the pituitary to GnRH, and (iii) plasma LH concentrations which should have occurred in response to TCDD-induced decreases in plasma testosterone concentrations. TCDD did not inhibit these compensatory responses in the absence of testicular hormones, while treatment of castrated rats with testosterone restored the ability of TCDD to prevent these increases. These findings demonstrate that TCDD alters the androgenic regulation of pituitary GnRH receptor number and pituitary responsiveness to GnRH stimulation. The pituitary is therefore a target organ for TCDD; whether a hypothalamic defect is also involved in the altered regulation of LH secretion was not resolved. The compensatory increases in pituitary GnRH receptor number and plasma LH concentration elicited by low plasma testosterone concentrations were inhibited by similar doses of TCDD (ED50 20 micrograms TCDD/kg for both responses). We concluded that TCDD increases the potency of androgens as feedback inhibitors of LH secretion by increasing their potency as regulators of both pituitary GnRH receptor number and GnRH responsiveness. This is the first demonstration that TCDD treatment (i) affects pituitary responsiveness to a hormone secreted by a peripheral organ (testosterone), and (ii) alters the regulation of pituitary responsiveness to a hypothalamic hormone (GnRH).     

Gonadotropin-releasing hormone antagonists

Hypothalamic gonadotropin-releasing hormone (GnRH) is a decapeptide that stimulates pituitary synthesis and secretion of gonadotropins and, therefore, gonadal hormones. GnRH antagonists, of which thousands have been formulated, inhibit the hormone from binding to its receptor, inducing a pharmacological hypophysectomy. Peptide derivations of GnRH and non-peptide compounds are both in clinical trials or approved for assisted reproduction. As these compounds reach the market, the use of antagonists might expand to treatment of other hormonally dependent diseases, hormonal male contraception and growth inhibition of extra-pituitary cancer cells expressing GnRH receptors.     

Identification of gonadotropin‐releasing hormone metabolites in greyhound urine

Gonadotropin‐releasing hormone (GnRH) is a 10‐residue peptide hormone that induces secretion of luteinizing hormone (LH) and follicle‐stimulating hormone into the blood from the pituitary gland. In males, LH acts on the testes to produce testosterone. The performance‐enhancing potential of testosterone makes administration of exogenous GnRH a concern in sports doping control. Detection of GnRH abuse is challenging owing to its rapid clearance from the body and its degradation in urine. Following recent investigations of GnRH abuse in racing greyhounds in New Zealand, we carried out a GnRH administration study in greyhounds in an attempt to identify GnRH metabolites that might provide more facile detection of GnRH abuse; little information is available on in vivo metabolites of exogenous GnRH in any species and none in dogs. We identified three C‐terminal GnRH metabolites in urine: GnRH 5–10, GnRH 6–10, and GnRH 7–10. These metabolites and intact GnRH, which was also detected in urine, were all excreted over a 1–3 h period after GnRH administration. Two of the GnRH metabolites – GnRH 5–10 and GnRH 6–10 – were more stable in urine than intact GnRH offering improved potential to detect GnRH administration. Copyright © 2017 John Wiley & Sons, Ltd.     

Pituitary gonadotroph-specific patterns of gene expression and hormone secretion

Pituitary gonadotrophs play a key role in reproductive functions by secreting luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The LH secretory activity of gonadotroph is controlled by hypothalamic gonadotropin-releasing hormone (GnRH) via GnRH receptors and is accompanied by only minor effects on high basal Lhb gene expression. The secretory profiles of GnRH and LH are highly synchronized, with the latter reflecting a depletion of prestored LH in secretory vesicles by regulated exocytosis. In contrast, FSH is predominantly released by constitutive exocytosis, and secretory activity reflects the kinetics of Fshb gene expression controlled by GnRH, activin, and inhibin. Here is a review of recent data to improve the understanding of multiple patterns of gonadotroph gene expression and hormone secretion.     

New developments in the use of peptide gonadotropin-releasing hormone antagonists versus agonists

Gonadotropin-releasing hormone (GnRH) stimulates the pituitary secretion of both luteinising hormone (LH) and follicle-stimulating hormone (FSH), and thus controls the hormonal and reproductive functions of the gonads. The blockade of the effects of GnRH may be sought for a variety of reasons; for example, to control premature LH surges and to reduce the cancellation rate with the aim of improving the pregnancy rate per treatment cycle or in the treatment of sex hormone-dependent disorders. Selective blockade of LH/FSH secretion and subsequent chemical castration have previously been achieved by desensitising the pituitary to continuously administered GnRH or by giving long-acting GnRH agonists. GnRH analogues are indicated for clinical situations in which the suppression of endogenous gonadotropins (precocious puberty, contraception and controlled ovarian hyperstimulation) or sexual steroids (endometriosis, prostate hyperplasia, cancer and uterine fibroids) is desired. The immediate suppression of the pituitary that is achieved by GnRH antagonists without an initial stimulatory effect is the main advantage of these compounds over the agonists. GnRH antagonists have been developed for clinical use with acceptable pharmacokinetic, safety and commercial profiles. In assisted reproduction, these compounds seem to be as effective as established therapy, but with shorter treatment times, less use of gonadotropic hormones, improved patient acceptance, and fewer follicles and oocytes. All of the current indications for GnRH agonist desensitisation may prove to be indications for a GnRH antagonist, including endometriosis, leiomyoma and breast cancer in women, benign prostatic hypertrophy and prostatic carcinoma in men, and central precocious puberty in children. However, the best clinical evidence has been in assisted reproduction and prostate cancer.     

New developments in the use of peptide gonadotropin-releasing hormone antagonists versus agonists

Gonadotropin-releasing hormone (GnRH) stimulates the pituitary secretion of both luteinising hormone (LH) and follicle-stimulating hormone (FSH), and thus controls the hormonal and reproductive functions of the gonads. The blockade of the effects of GnRH may be sought for a variety of reasons; for example, to control premature LH surges and to reduce the cancellation rate with the aim of improving the pregnancy rate per treatment cycle or in the treatment of sex hormone-dependent disorders. Selective blockade of LH/FSH secretion and subsequent chemical castration have previously been achieved by desensitising the pituitary to continuously administered GnRH or by giving long-acting GnRH agonists. GnRH analogues are indicated for clinical situations in which the suppression of endogenous gonadotropins (precocious puberty, contraception and controlled ovarian hyperstimulation) or sexual steroids (endometriosis, prostate hyperplasia, cancer and uterine fibroids) is desired. The immediate suppression of the pituitary that is achieved by GnRH antagonists without an initial stimulatory effect is the main advantage of these compounds over the agonists. GnRH antagonists have been developed for clinical use with acceptable pharmacokinetic, safety and commercial profiles. In assisted reproduction, these compounds seem to be as effective as established therapy, but with shorter treatment times, less use of gonadotropic hormones, improved patient acceptance, and fewer follicles and oocytes. All of the current indications for GnRH agonist desensitisation may prove to be indications for a GnRH antagonist, including endometriosis, leiomyoma and breast cancer in women, benign prostatic hypertrophy and prostatic carcinoma in men, and central precocious puberty in children. However, the best clinical evidence has been in assisted reproduction and prostate cancer.     

Non-peptidic GnRH receptor antagonists

Gonadotropin-releasing hormone (GnRH) or luteinizing hormone-releasing hormone (LHRH) is a decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) hypothalamic hormone that acts upon 7-trans membrane spanning GnRH receptors in the pituitary. This action leads to the secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) that in turn act on the reproductive organs regulating gonadal steroid production, spermatogenesis and follicular development. Peptidic agonists of the GnRH receptor have been known for many years and are currently employed therapeutically in the treatment of prostate and breast tumours, uterine fibroids, precocious puberty, endometriosis, premenstrual syndrome, contraception and infertility. Peptidic antagonists to date have only been employed commercially in the treatment of infertility during assisted reproductive therapy; however, many peptidic antagonists are currently in late stage development for many of the aforementioned indications. Whilst peptidic agonists and antagonists of the GnRH receptor have been discovered and exploited clinically, they are limited to predominantly parenteral administration due to their poor oral bioavailability. Recently, several small molecule GnRH antagonist series have been discovered offering the prospect of orally active therapeutics based on GnRH receptor antagonism. This article will review the current medicinal chemistry literature and structure activity relationships known for non-peptidic GnRH receptor antagonists.