青少年性腺功能减退症药物治疗的选择

完整的下丘脑-垂体-性腺轴功能的调节机制是正常的性腺发育和功能维持的基础．这一轴系中任意环节出现异常均可以导致性腺功能减退。青少年性功能减退患者的致病原因与成人患者并无显著区别．大致可分为先天性和获得性两大类。青少年性腺功能减退的患者．如无合并其他疾病或躯体畸形,在青春期前一般较难被发现．大部分患者由于青春期延迟而就诊。对于青少年性腺功能减退的患者．其首要治疗目的应为启动并完成正常的青春期发育,同时获得理想的成年身高。本文针对青少年性腺功能减退症药物治疗的选择进行综述。     

低促性腺激素性性腺功能减退症患者KAL-1基因突变分析

目的探讨云南地区低促性腺激素性性腺功能减退症（HH）患者与KAL-1基因突变的相关性。方法采用病例-对照研究、聚合酶链反应和基因测序方法对4例Kallmann综合症（Ks）患者、5例特发性低促性腺激素性性腺功能减退症（IHH）患者及10例正常健康男性对照组基因组DNA之KAL-1基因14个外显子分别进行突变分析。结果在4例Ks患者中,2例发现存在KAL-1基因突变,其中1例发现KAL-1基因内第6外显子缺失,另1例发现KAL-1基因第5外显子在基因位点883缺失-碱基“A”,使遗传密码子发生移码性突变。在5例IHH及10例正常健康男性对照组中未发现有KAL-1基因突变。结诊KAL-1基因突变是本地区人群低促性腺激素性性腺功能减退症患者易感因素之一。     

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。     

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。     

特发性低促性腺激素型性腺功能减退2例报告

特发性低促性腺激素型性腺功能减退症（IHH）是指病因不明的下丘脑或垂体病变引起促性腺激素释放激素（GnRH）或促性腺激素的缺乏,不能刺激靶性腺发育而导致第二性征发率异常。1临床资料例1,男,24岁,高中。因婚居未避孕未育1＋年来我院诊治。患者声音细,外生殖器小于同龄男性。既往体健,系足月平产,母乳喂养;父母非近亲结婚,无家族遗传病史。入院体格检查：     

性腺功能减退症治疗疗效的评估

性腺功能减退症是各种原因导致的下丘脑．垂体-性腺轴功能受损而引起的一类疾病，其临床症状因病因、程度和起病早晚而有所不同．可根据患者的病史、体格检查．实验室检查、影像学检查进行诊断与鉴别诊断。早期诊断是性腺功能减退症治疗的关键。治疗方案的选择因病因、性别、年龄等有所差异，根据不同需要可以选择性激素．促性腺激素以及GnRH脉冲泵治疗等。治疗过程中的疗效评估有助于及时调整治疗方案．以维持性腺功能、促进第二性征发育．改善生活质量，尽可能恢复和重建生育能力。     

特发性低促性腺激素型性腺功能低下综合征一例报告

特发性低促性腺激素型性腺功能低下综合症(Kall-mann syndrome)是一种较少见的先天性疾病,表现为促性腺激素释放激素(Gonadotropin releasing hormone,GnRH)降低或缺乏。国内报道较少,我科于2007年3月收治1例,现报告如下。1临床资料患者罗某,男性,17岁,未婚,因双侧睾丸位置异常     

注射用尿促性素-绒毛膜促性腺激素替代治疗低促性腺激素性闭经12例

由于垂体功能衰竭导致的低促性腺激素性闭经是无排卵、闭经与不孕症的常见原因.应用注射用尿促性素(HMG)、绒毛膜促性腺激素(HCG)替代治疗,促使月经来潮、排卵和妊娠,在国内外均已有报道.本文自2000年8月至2002年10月,共收治低促性腺激素性闭经患者12例,进行了14个促排卵周期的治疗,现将治疗结果报告如下.     

甲状腺功能减退症的临床治疗效果观察

目的 探讨甲状腺功能减退症的临床治疗研究进展.方法 选择2009年8月～2012年8月来本院就诊的83例原发性甲状腺功能减退症患者,根据年龄、病情程度和个体差异分为A组和B组,A组给予左旋甲状腺素片部分替代治疗,B组给予激素完全替代治疗,选择40例患者联合中药治疗,其中A组14例,B组26例.通过观察患者治疗前后血清T3、T4和TSH的变化来评估分析不同方案治疗的总体疗效.结果 A、B组中合并中药组的总有效率明显高于非合并中药组,差异有统计学意义（P＜0.05）;A、B组治疗后FT3、FT4均明显升高,TSH治疗后明显降低,差异有统计学意义（P＜0.01）.结论说明中成药的联合应用能良好改善患者的临床症状、体征,良好改善患者的病情和生活质量;两组不同激素替代治疗方案明显改善了患者血清FT3、FT4和TSH值,使其达到较为适宜范围,良好改善了患者的病情.     

HMG小剂量递增法治疗特发性低促性腺激素性性腺功能减退性不孕1例

患者,2 4岁,主因原发性闭经就诊。患者出生时未见异常,外阴为女性。13岁起出现乳房发育,身高和阴毛发育未见异常。一直无月经,曾在外院应用雌孕激素周期治疗。现为婚后2a ,男方精液常规正常,有正常性生活未怀孕。既往无病史记载。体格检查:身高16 5cm ,体重6 2kg ,第二性征发育尚好,阴毛分布呈女性型,大小阴唇发育正常,阴道(- ) ,宫颈小,宫体前位,约4cm×3cm ,双附件(- )。性激素系列检查(闭经5个月) :E2 :4 5 .31pg/mL ,FSH :0 .39mIU/mL ,LH :0 .2mIU/mL ,PRL :4 .14ng/mL ,PROG :3.85ng/mL ,TEST :0 .2 9ng/mL。妇科B超:子宫…     

The safety of available treatments of male hypogonadism in organic and functional hypogonadism

Introduction: In the case of primary male hypogonadism (HG), only testosterone (T) replacement therapy (TRT) is possible whereas when the problem is secondary to a pituitary or hypothalamus alteration both T production and fertility can be, theoretically, restored. We here systematically reviewed and discussed the advantages and limits of medications formally approved for the treatment of HG.

Areas covered: Data derived from available meta-analyses of placebo controlled randomized trials (RCTs) were considered and analyzed. Gonadotropins are well-toleratedand their use is mainly limited by higher costs and a more cumbersome treatment schedule than TRT. Available RCTs on TRT suggest that cardiovascular (CV) and venous thromboembolism risk is not a major issue and that prostate safety is guaranteed. The risk of increased hematocrit is mainly limited to the use of short terminjectable preparations.

Expert opinion: In the last few years the concept of ‘organic’ irreversible HG and ‘functional’ or age- and comorbidity-related HG has been introduced. This definition is not evidence-based. The majority of RCTs enrolled patients with ‘functional’ HG. Considering the significant improvement in body composition, glucose metabolism and sexual activity, TRT should not be limited to ‘organic’ HG, but also offered for ‘functional’.     

The latest options and future agents for treating male hypogonadism

Exogenous testosterone has long been used in medicine as a pharmaceutical agent. Its use in hypogonadism is well characterized and its development as a drug has undergone several modifications in an attempt to achieve clinical success. As native testosterone is rapidly degraded, modified analogs have been developed to obtain a better pharmacokinetic profile. The developmental goals of testosterone analogs have evolved since its first introduction as an orally available form to longer acting and more stable forms such as injectables, depots and transdermal therapies. Several modalities of testosterone replacement are presently available, each differentiated by their route of delivery, half life, cost and ability to deliver physiologic levels of testosterone. As hypogonadism is often a life-long condition, physicians are compelled to use an appropriate therapy that best matches the needs of their patients. An ideal testosterone therapy should be able to deliver physiologic levels of testosterone and be safe, simple to use and cost effective. Present trends show transdermal therapies (gels and patches) along with long-acting injectables, such as Nebido, are quickly replacing intramuscular testosterone modalities. Compounds such as dihydrotestosterone, human chorionic gonadotropin, aromatase inhibitors and clomiphene are presently being studied in specific subgroups of men. Additionally, several new compounds, such as selective androgen-receptor modulators and 7-alpha-methyl-19-nortestosterone, are being developed to target androgen receptors in specific tissues. A further understanding of the androgen receptor and subsequent discovery of targeted drugs may yield more individualized treatment modalities. This will enhance the effectiveness of available therapies, while mitigating their undesirable effects.     

The pharmacotherapy of male hypogonadism besides androgens

Introduction: Adulthood male hypogonadism (HG) is the most common form of HG. Although testosterone (T) replacement therapy (TRT) is the most common way of treating HG, other options are available depending on patient’s needs and expectations.

Areas covered: We analyze alternative options to TRT as a medical intervention in treating HG. Gonadotropin (Gn) therapy is the treatment of choice in men with secondary HG (sHG), who require fertility. Gonadotropin-releasing hormone therapy represents an alternative to Gn for inducing spermatogenesis in patients with sHG, however, its use is limited by the poor patient compliance and high cost. In obese HG men, lifestyle modifications and, in particular, weight loss should be the first step. Recent data suggest that antiestrogens represent a successful treatment for sHG. Other potential therapeutic options include the stimulation of hypothalamic activity (i.e., kisspeptin and neurokinin-B agonists). Conversely, the possibility of increasing Leydig cell steroid production, independently from Gn stimulation, seems unreliable.

Expert opinion: Understanding the nature of male HG and patient’s needs are mandatory before choosing among treatment options. For primary HG only TRT is advisable, whereas for the secondary form several alternative possibilities can be offered.     

The latest options and future agents for treating male hypogonadism

Exogenous testosterone has long been used in medicine as a pharmaceutical agent. Its use in hypogonadism is well characterized and its development as a drug has undergone several modifications in an attempt to achieve clinical success. As native testosterone is rapidly degraded, modified analogs have been developed to obtain a better pharmacokinetic profile. The developmental goals of testosterone analogs have evolved since its first introduction as an orally available form to longer acting and more stable forms such as injectables, depots and transdermal therapies. Several modalities of testosterone replacement are presently available, each differentiated by their route of delivery, half life, cost and ability to deliver physiologic levels of testosterone. As hypogonadism is often a life-long condition, physicians are compelled to use an appropriate therapy that best matches the needs of their patients. An ideal testosterone therapy should be able to deliver physiologic levels of testosterone and be safe, simple to use and cost effective. Present trends show transdermal therapies (gels and patches) along with long-acting injectables, such as Nebido^®, are quickly replacing intramuscular testosterone modalities. Compounds such as dihydrotestosterone, human chorionic gonadotropin, aromatase inhibitors and clomiphene are presently being studied in specific subgroups of men. Additionally, several new compounds, such as selective androgen-receptor modulators and 7-α-methyl-19-nortestosterone, are being developed to target androgen receptors in specific tissues. A further understanding of the androgen receptor and subsequent discovery of targeted drugs may yield more individualized treatment modalities. This will enhance the effectiveness of available therapies, while mitigating their undesirable effects.     

Emerging medication for the treatment of male hypogonadism

INTRODUCTION: Since the phenotype and clinical need of the hypogonadal individuals changes dramatically over time, versatile therapies are needed. AREAS COVERED: The authors review the available evidence on possible therapies. EXPERT OPINION: In the case of primary hypogonadism starting early in life, substitution with testosterone (T) is the only choice. For secondary congenital hypogonadism, we recommend starting with gonadotrophins to allow the testes to reach pubertal size. Thereafter, T replacement therapy can be administered until fertility is desired. At that time, gonadotrophins should be employed until fathering occurs. Antiestrogens are an alternative, however, their efficacy has not been adequately tested. In the presence of increased estrogen production symptoms (breast tenderness and gynecomastia), a short-term trial with non-aromatizable androgens (dihydrotestosterone mesterolone or oxandrolone) could be advisable. However, after a few months of therapy, switching to other aromatizable preparations is recommended, to prevent bone loss. When prostate safety is concerned, the use of steroidal or non-steroidal selective androgen receptor modulators that are less susceptible to 5α reduction might be advisable. An attractive possibility is the combined use of testosterone with 5α inhibitors. Theoretically, also estrogen receptor-beta ligands could be employed, however the development of these compounds, although promising, is still in its infancy.     

Emerging medication for the treatment of male hypogonadism

Introduction: Since the phenotype and clinical need of the hypogonadal individuals changes dramatically over time, versatile therapies are needed.

Areas covered: The authors review the available evidence on possible therapies.

Expert opinion: In the case of primary hypogonadism starting early in life, substitution with testosterone (T) is the only choice. For secondary congenital hypogonadism, we recommend starting with gonadotrophins to allow the testes to reach pubertal size. Thereafter, T replacement therapy can be administered until fertility is desired. At that time, gonadotrophins should be employed until fathering occurs. Antiestrogens are an alternative, however, their efficacy has not been adequately tested. In the presence of increased estrogen production symptoms (breast tenderness and gynecomastia), a short-term trial with non-aromatizable androgens (dihydrotestosterone mesterolone or oxandrolone) could be advisable. However, after a few months of therapy, switching to other aromatizable preparations is recommended, to prevent bone loss. When prostate safety is concerned, the use of steroidal or non-steroidal selective androgen receptor modulators that are less susceptible to 5α reduction might be advisable. An attractive possibility is the combined use of testosterone with 5α inhibitors. Theoretically, also estrogen receptor-beta ligands could be employed, however the development of these compounds, although promising, is still in its infancy.     

Opioids and hypogonadism

Detailed reports of hypogonadotropic hypogonadism in patients receiving morphine analgesia were published in 2010. Symptoms included flushing and sweating, amenorrhoea, impotence and decreased libido. Epidemiological studies have examined a possible link between hypogonadism and opioid use, in both patients and drug addicts. Statistically significant decreases in plasma hormone concentrations were found, with lower testosterone and LH levels in men, and lower oestradiol, progesterone, LH and FSH levels in women. Animal studies have provided consistent results. It is suspected that opioids affect the hypothalamic-pituitary axis, inhibiting LH secretion. Patients should be warned of this risk. If signs of hypogonadism occur in a patient taking an opioid, the benefits and harms of treatment should be reassessed. If possible, the dose should be reduced or the opioid withdrawn.