An update on male hypogonadism therapy

Introduction: Men who have symptoms associated with persistently low serum total testosterone level should be assessed for testosterone replacement therapy.

Areas covered: Acute and chronic illnesses are associated with low serum testosterone and these should be recognized and treated. Once the diagnosis of male hypogonadism is made, the benefits of testosterone treatment usually outweigh the risks. Without contraindications, the patient should be offered testosterone replacement therapy. The options of testosterone delivery systems (injections, transdermal patches/gels, buccal tablets, capsules and implants) have increased in the last decade. Testosterone improves symptoms and signs of hypogonadism such as sexual function and energy, increases bone density and lean mass and decreases visceral adiposity. In men who desire fertility and who have secondary hypogonadism, testosterone can be withdrawn and the patients can be placed on gonadotropins. New modified designer androgens and selective androgen receptor modulators have been in preclinical and clinical trials for some time. None of these have been assessed for the treatment of male hypogonadism.

Expert opinion: Despite the lack of prospective long-term data from randomized, controlled clinical trials of testosterone treatment on prostate health and cardiovascular disease risk, the available evidence suggests that testosterone therapy should be offered to symptomatic hypogonadal men.     

Testosterone undecanoate in the treatment of male hypogonadism

Importance of the field: Testosterone undecanoate (TU) represents an exciting new testosterone replacement therapy for hypogonadal men due to its convenient dosing schedule and favorable pharmacokinetic and safety profiles.

Areas covered in this review: Clinical, pharmacokinetic and safety characteristics of TU will be reviewed. The characteristics of currently approved testosterone therapies will be reviewed and compared with those of TU in order to determine which therapy most appropriately meets the clinical objective of properly matching a patient with a therapy that is best able to deliver physiological levels of testosterone for prolonged periods of time, while at the same time being safe, effective, inexpensive, simple to use, and with few side effects.

What the reader will gain: TU represents the first long-acting injectable with an excellent safety profile that can be administered only four times annually to produce stable levels of testosterone. Long-term studies have validated the clinical efficacy of TU in maintaining therapeutic levels of testosterone. Patient preference for the convenient dosing schedule might also lead to better compliance and therapeutic benefit. No serious side effects have been noted with the use of TU, including long-term data on patients treated with TU over 8 years.

Take home message: TU is both a desirable and safe option for the treatment of hypogonadal men. Patients will benefit from the stable testosterone levels and fewer required injections, while achieving the desired benefits of androgen replacement.     

Risks versus benefits of testosterone therapy in elderly men.

'Andropause', like menopause, has received significant attention in recent years. It results in a variety of symptoms experienced by the elderly. Many of these symptoms are nonspecific and vague. For this reason, many authors have questioned the value of androgen replacement in this population. Also in dispute is the normal cutoff level for testosterone beyond which therapy should be initiated, and whether to measure free or total testosterone. Testosterone levels decline with age, with the lowest level seen in men older than 70 years. This age-related decline in testosterone levels is both central (pituitary) and peripheral (testes) in origin. With aging, there is also a loss of circadian rhythm of testosterone secretion and a rise in sex hormone binding globulin (SHBG) levels. Total testosterone level is the best screening test for patients with suspected hypogonadism. If the total testosterone concentration is low, free testosterone levels should be obtained. Prostate cancer remains an absolute contraindication to androgen therapy. Testosterone replacement results in an improvement in muscle strength and bone mineral density. Similar effects are observed on the haematopoietic system. Data on cognition and lipoprotein profiles are conflicting. Androgen therapy can result in polycythemia and sleep apnoea. These adverse effects can be deleterious in men with compromised cardiac reserve. We recommend that elderly men with symptoms of hypogonadism and a total testosterone level <300 ng/dl should be started on testosterone replacement. This review discusses the pros and cons of testosterone replacement in hypogonadal elderly men and attempts to answer some of the unanswered questions. Furthermore, emphasis is made on the regular follow-up of these patients to prevent the development of therapy-related complications.     

Response to degarelix after resistance to luteinizing hormone-releasing hormone agonist therapy for metastatic prostate cancer

Androgen deprivation with a luteinizing hormone-releasing hormone (LH-RH) agonist is the standard treatment for patients with metastatic prostate cancer who prefer nonsurgical options. Therapy with these agents is usually successful in achieving and maintaining castrate levels (< 50 ng/dl) of serum testosterone, but failures have been reported in up to 10% of patients. Traditionally, these patients are offered surgical castration with bilateral orchiectomy. However, the novel LH-RH antagonists may offer a nonsurgical alternative. We describe two patients with advanced prostate cancer who failed to achieve castrate levels of testosterone while on an LH-RH agonist, but subsequently responded to the LH-RH antagonist, degarelix. The first patient is a 63-year-old man who was treated with leuprolide for metastatic prostate cancer. He initially responded with prostate-specific antigen (PSA) that fell to 0.6 ng/ml. However, after 15 months of therapy, his PSA rose to 18.3 ng/ml and his testosterone was noted to be 208 ng/dl. He was switched to degarelix, and 4 weeks later his testosterone was adequately suppressed at 16 ng/dl. The second patient is a 41-year-old man with metastatic prostate cancer who was started on leuprolide, but after 3 months of therapy, was found to have a rising PSA and a testosterone of 96 ng/dl. Four weeks after switching to degarelix, his testosterone was 18 ng/dl and his PSA decreased concordantly. With continued monthly injections of degarelix, his testosterone has consistently remained to be at less than 20 ng/dl over 7 months of follow-up.     

Current and future testosterone delivery systems for treatment of the hypogonadal male

BACKGROUND: Hypogonadism is manifest in all age groups, and a growing elderly population is requiring treatment for testosterone deficiency, presenting new safety challenges, as many of these individuals present with comorbidities and significant risk profiles. OBJECTIVE: To discuss testosterone replacement modalities, their advantages and disadvantages, and provide a discussion of safety issues. METHODS: We reviewed the literature regarding testosterone replacement therapy and have provided a summary of our most outstanding findings. CONCLUSION: Potential benefits of testosterone replacement therapy include increased lean body mass, heightened libido, increased bone density and elevation of mood. Some disadvantages are clearly defined, while others require further investigation. Patient and physician must cooperate to agree on an individual patient's most appropriate and tolerable route of administration.     

两种睾丸活检术前后血清睾酮水平的检测及临床意义

目的探讨两种睾丸活检方法：切开活检和穿刺活检对血清睾酮影响的差别。方法 56例男性不育患者分为两组,分别行传统切开睾丸活检和穿刺活检。在术前和术后3、6、12个月采静脉血测定血清睾酮水平。结果两组患者睾丸活检术后血清睾酮均下降,术后6个月达到最低水平,术后12个月逐渐恢复,但未达到正常水平。切开活检组术后睾酮水平显著低于穿刺活检组。结论睾丸穿刺活检对血清睾酮水平影响小,优于切开活检,但睾丸活检术后均需常规补充外源性的雄激素。     

Androgen deficiency as a predictor of metabolic syndrome in aging men: an opportunity for intervention?

The prevalence of metabolic syndrome is increasing globally and is an important risk factor for the development of cardiovascular disease. Longitudinal population studies have found that low testosterone status in men is a risk factor for the later development of metabolic syndrome. Men with metabolic syndrome and type 2 diabetes mellitus have a higher incidence of hypotestosteronaemia. Furthermore, in men, testosterone levels are inversely associated with the degree of carotid and aortic atherosclerosis. Early interventional, short-term studies have shown that testosterone replacement therapy has a beneficial effect on visceral obesity, insulin sensitivity, glycaemic control and lipid profiles in men with diagnosed hypogonadism with and without diabetes. The effect of testosterone therapy on atherogenesis in men is unknown; however, animal studies have shown that testosterone is atheroprotective and can ameliorate the degree of atherosclerosis. Testosterone is an arterial vasodilator and has been shown to improve myocardial ischaemia in men with coronary artery disease. This review discusses the role that testosterone may play in the pathogenesis of metabolic syndrome in men and also examines the potential role of testosterone replacement therapy in this condition.     

Nebido: a long-acting injectable testosterone for the treatment of male hypogonadism

Over the last six decades, tremendous strides have been made in the development of safe, efficacious and 'patient-friendly' modalities of testosterone replacement therapy in men. The most recent forms of androgen replacement that are in widespread use include testosterone patch and gel. These preparations are convenient in their use and deliver a physiological amount of testosterone. Although these transdermal preparations are gaining popularity, many hypogonadal men still receive treatment with intramuscular esters. Testosterone enanthate remains the most commonly prescribed ester. Although testosterone esters are efficacious in terms of improving bone and muscle mass, they possess unfavourable pharmacokinetics that result in fluctuations in the mood, energy and sexual function of patients. Furthermore, these esters need to be injected every 2-4 weeks. Hence, there has been a need to develop long-acting esters that can be administered infrequently and deliver a physiological amount of testosterone without major fluctuations. Recently, injectable testosterone undecanoate (Nebido) has become available in Europe and will soon be marketed in south America, Asia and Australia. In this paper, the structure, pharmacokinetics, efficacy and side-effect profile of testosterone undecanoate will be reviewed and also compared with other existing testosterone esters.     

Nebido: a long-acting injectable testosterone for the treatment of male hypogonadism

Over the last six decades, tremendous strides have been made in the development of safe, efficacious and ‘patient-friendly’ modalities of testosterone replacement therapy in men. The most recent forms of androgen replacement that are in widespread use include testosterone patch and gel. These preparations are convenient in their use and deliver a physiological amount of testosterone. Although these transdermal preparations are gaining popularity, many hypogonadal men still receive treatment with intramuscular esters. Testosterone enanthate remains the most commonly prescribed ester. Although testosterone esters are efficacious in terms of improving bone and muscle mass, they possess unfavourable pharmacokinetics that result in fluctuations in the mood, energy and sexual function of patients. Furthermore, these esters need to be injected every 2 – 4 weeks. Hence, there has been a need to develop long-acting esters that can be administered infrequently and deliver a physiological amount of testosterone without major fluctuations. Recently, injectable testosterone undecanoate (Nebido^®) has become available in Europe and will soon be marketed in south America, Asia and Australia. In this paper, the structure, pharmacokinetics, efficacy and side-effect profile of testosterone undecanoate will be reviewed and also compared with other existing testosterone esters.     

Current and future testosterone delivery systems for treatment of the hypogonadal male

Background: Hypogonadism is manifest in all age groups, and a growing elderly population is requiring treatment for testosterone deficiency, presenting new safety challenges, as many of these individuals present with comorbidities and significant risk profiles. Objective: To discuss testosterone replacement modalities, their advantages and disadvantages, and provide a discussion of safety issues. Methods: We reviewed the literature regarding testosterone replacement therapy and have provided a summary of our most outstanding findings. Conclusion: Potential benefits of testosterone replacement therapy include increased lean body mass, heightened libido, increased bone density and elevation of mood. Some disadvantages are clearly defined, while others require further investigation. Patient and physician must cooperate to agree on an individual patient's most appropriate and tolerable route of administration.     

Andropause: an androgen deficiency state in the ageing male

An age-related decline in circulating testosterone levels has been shown to occur in the adult male population starting as early as middle age and continuing on into old age. This decline in testosterone has been associated with a number of changes in body composition and sexual performance in the male that are directly attributable to an androgen deficiency state, which can be restored by the use of testosterone replacement therapy. The term 'andropause' has been used to describe this gradual drop in testosterone in the ageing male and is characterised by different endocrine, somatic and psychic changes that become more pronounced as the male gets older. For some males, the adjustment of circulating testosterone levels with replacement therapy to levels seen in young men can improve physical performance, induce a sense of well-being and restore the androgen-dependent sex drive that declines with ageing.     

Testosterone replacement therapy in obese males

Controversy surrounds testosterone replacement therapy in obese ageing due to no generally accepted lower limits of normal testosterone level and high prevalence of hypogonadal symptoms in the ageing male population and the non-specific nature of these symptoms. Late onset hypogonadism is a clinical and biochemical syndrome associated with advancing age, often coexisting with obesity and metabolic syndrome. High fat and carbohydrates (fructose) consumption is responsible for development of obesity and metabolic syndrome which is one of risk factors for hypogonadism in older men. High fructose intake has been shown to cause dyslipidemia and to impair hepatic insulin sensitivity. Obesity and lack of physical activity negatively influence testosterone level. Low testosterone level should be regarded as an effect of obesity, but reverse relationship has not been proved yet. The management of late-onset hypogonadism symptoms has to be treated by a change of a life style and prevented with healthy nutrition and physical activity. The question related to rational indications for testosterone replacement therapy in obese males seems to be still actual.     

Treating erectile dysfunction in renal transplant recipients

Erectile dysfunction is common in male kidney transplant recipients. Interference with the physiology of erections can be attributed to recipient co-morbidities, the renal transplant operation, medication adverse effects, relationship problems and changes in mental health. A treatment-oriented evaluation of erectile dysfunction allows the development of treatment plans that are patient-specific. Hypo-gonadal men whose hormone parameters do not improve after renal transplantation may respond to testosterone replacement therapy. Use of recommended doses of the phosphodiesterase-5 inhibitor sildenafil does not significantly modify trough concentrations of the calcineurin inhibitors ciclosporin and tacrolimus or result in impaired renal allograft function. Tacrolimus has been shown to increase the peak concentration and prolong the elimination half-life of sildenafil in kidney transplant recipients. Daily administration of sildenafil has resulted in decreased blood pressure in kidney transplant recipients with treated hypertension and tacrolimus immunosuppression. Intracavernosal injections of alprostadil, with or without papaverine and phentolamine, are effective treatments for erectile dysfunction after renal transplantation and have not resulted in alterations of ciclosporin concentrations or in deterioration of renal function. Penile prostheses can be successfully implanted after pelvic organ transplantation without significant risk of infection.     

Testosterone: its role in development of prostate cancer and potential risk from use as hormone replacement therapy

Evidence from studies in patients with prostate cancer of intermittent hormone therapy combined with results from rechallenge of hormone resistant patients with testosterone demonstrate that the majority of prostate cancers retain a similar degree of dependence on male sex hormone milieu as normal prostate cells. Yet there has so far been no conclusive evidence, despite 34 studies, that levels of circulating testosterone in individuals developing prostate cancer are higher than in controls. The aim of this article was to critically evaluate this evidence and seek clues to other mechanisms whereby sex hormones could influence the development of prostate cancer. Additionally, epidemiological data were examined to investigate the interplay between sex hormone levels and environmental factors to help understand the development of prostate cancer and identify a safe way to provide hormone replacement therapy (HRT). Three overviews provide similar evidence that there is no significant difference in mean testosterone levels between patients and controls. However in the most recent review of studies, though there was no difference in means between cases and controls, there was a significant risk (adjusted odds ratio 2.34) for individuals identified by comparing incidence of prostate cancer in men in the upper and lower quartile of testosterone level. This report, taken with epidemiological data demonstrating that prostate cancer risk is increased by early age of onset of sexual activity and multiple nonspecific sexually transmitted diseases (STDs), has led to the hypothesis that the link between sex hormones and prostate cancer is indirect. Those individuals with high testosterone levels were more at risk of acquisition of multiple nonspecific STDs. This promotes transformation of prostate cells and damage to Leydig cells in the testis leading to there being no difference in testosterone compared with controls by the time the tumour is diagnosed. Because of the observed relationship between testosterone and prostate cancer development there has been anxiety about marketing HRT for men. Two observations support the view that the prostate cancer risks from use of testosterone hormone replacement may not be as great as first feared. Firstly, prostate cancers arising in men with low serum testosterone levels are more malignant and frequently nonresponsive to hormones. Secondly, breast cancers diagnosed in women on HRT though increased in number are less malignant possibly because of enhanced sensitivity to hormone therapy, and the situation may prove to be analogous with prostate cancer and testosterone replacement.     

Topical testosterone supplementation for the treatment of male hypogonadism

Age-related hormonal decline is gradual and less recognized in men than in women. Symptoms are oftentimes ignored and non-specific. Fatigue, lack of concentration, mood swings, decreased sexual desire, erectile dysfunction, infertility, hair loss, reduced muscle and bone mass, and weight gain are a few of the symptoms of male hypogonadism. This disorder is linked to reduction in quality of life, and poorer health outcomes as it may increase the risk for cardiovascular disease, diabetes mellitus, metabolic syndrome, Alzheimer's disease and premature death. Different modalities of testosterone replacement therapy have evolved over 70 years, and sales continue to grow. Each preparation is differentiated by route of delivery, ease of use, cost and pharmacokinetics. Topical/transdermal testosterone replacement therapy, including patches and gels, are the most modern formulations on the market. These are more expensive treatments, but yield more physiological concentrations of testosterone. Restoration of testosterone levels to the eugonadal range reverses signs and symptoms of hypogonadism, except for infertility, and may alleviate co-morbidities associated with hypogonadism. Patient understanding of and compliance with both treatment and monitoring are of utmost importance to achieve clinical success with maximum benefit and minimum risk. The aim of our review is to summarize the indications, contraindications, benefits and risks of testosterone replacement therapy as they relate to transdermal administration. Further, we compare the various testosterone preparations, focusing on the newest topical/transdermal routes of administration that are currently available.     

Replacing testosterone in men

Around 1 in 200 men have abnormally low levels of circulating testosterone that result in hypogonadism. Most of these men should be offered testosterone replacement therapy. Here we outline the rationale for such treatment and the different preparations available. We do not discuss the use of testosterone to induce pubertal development in prepubertal males with hypogonadism.     

Testosterone patch: new drug. Don't use to stimulate women's sexual desire

(1) A new disorder, 'hypoactive sexual desire disorder' (HSDD), has recently been promoted, just around the same time as the market release of testosterone patches. (2) Clinical evaluation of the testosterone patches is mainly based on two trials lasting 24 weeks and including a total of 1095 women who had undergone bilateral ovariectomy and hysterectomy and were also taking oestrogen replacement therapy. The indications for ovariectomy were not reported. (3) The average number of 'satisfying sexual activities' was about 3 during the 4 weeks that preceded the trial. It only increased slightly, in absolute terms, in the testosterone group compared to the placebo group (about 5 versus 4) during the last 4 weeks of the trial. (4) Scores on some rating scales improved slightly in the testosterone group, but their clinical relevance is unknown. (5) Acne, hirsutism, hair loss and deepening of the voice occurred more frequently in women using testosterone patches than in women on placebo. In about 30% to 60% of affected women, these adverse effects failed to resolve on treatment cessation. (6) The trials were too short to assess potential long-term risks, especially risks of cardiovascular events and cancer, in women who are also using oestrogen replacement therapy. (7) In practice, the risks associated with testosterone do not justify its use, particularly since the benefits are uncertain and at best modest. Sexual desire is governed by complex mechanisms. It is better to help women to understand and deal with the sources of their dissatisfaction than to expose them to the adverse effects of hormone therapy.     

Testosterone Ethosomes for Enhanced Transdermal Delivery

Physiological decrease in testosterone levels in men with age causes various changes with clinical significance. Recent testosterone replacement therapy is based mainly on transdermal nonpatch delivery systems. These products have the drawback of application on extremely large areas to achieve required hormone blood levels. The objective of the present study was to design and test a testosterone nonpatch formulation using ethosomes for enhanced transdermal absorption. The ethosomal formulation was characterized by transmission electron microscopy and dynamic light scattering for structure and size distribution and by ultracentrifugation for entrapment capacity. To evaluate the feasibility of this delivery system to enhance testosterone permeation through the skin, first the systemic absorption in rats was compared with a currently used gel (AndroGel®). Further, theoretical estimation of testosterone blood concentration following ethosomal application in men was made. For this purpose, in vitro permeation experiments through human skin were performed to establish testosterone skin permeation values. In the design of these experiments, testosterone solubility in various solutions was measured and the effect of the receiver medium on the skin barrier function was assessed by confocal laser scanning microscopy. Theoretical estimation shows that testosterone human plasma concentration value in the upper part of the physiological range could be achieved by application of the ethosomal formulation on an area of 40 cm². This area is about 10 times smaller than required with current nonpatch formulations. Our work shows that the ethosomal formulation could enhance testosterone systemic absorption and also be used for designing new products that could solve the weaknesses of the current testosterone replacement therapies.     

Testosterone ethosomes for enhanced transdermal delivery

Physiological decrease in testosterone levels in men with age causes various changes with clinical significance. Recent testosterone replacement therapy is based mainly on transdermal nonpatch delivery systems. These products have the drawback of application on extremely large areas to achieve required hormone blood levels. The objective of the present study was to design and test a testosterone nonpatch formulation using ethosomes for enhanced transdermal absorption. The ethosomal formulation was characterized by transmission electron microscopy and dynamic light scattering for structure and size distribution and by ultracentrifugation for entrapment capacity. To evaluate the feasibility of this delivery system to enhance testosterone permeation through the skin, first the systemic absorption in rats was compared with a currently used gel (AndroGel®). Further, theoretical estimation of testosterone blood concentration following ethosomal application in men was made. For this purpose, in vitro permeation experiments through human skin were performed to establish testosterone skin permeation values. In the design of these experiments, testosterone solubility in various solutions was measured and the effect of the receiver medium on the skin barrier function was assessed by confocal laser scanning microscopy. Theoretical estimation shows that testosterone human plasma concentration value in the upper part of the physiological range could be achieved by application of the ethosomal formulation on an area of 40 cm². This area is about 10 times smaller than required with current nonpatch formulations. Our work shows that the ethosomal formulation could enhance testosterone systemic absorption and also be used for designing new products that could solve the weaknesses of the current testosterone replacement therapies.     

Gender as a regulator of atherosclerosis in murine models

The risk of development and progression of atherosclerosis is different between males and females. Premenopausal women have a lower risk of developing atherosclerosis and cardiovascular disease than men. However, after the onset of menopause the protection associated with gender is lost and the risk of women developing atherosclerosis gradually approaches that of men. In an effort to treat the elevated risk of cardiovascular disease in postmenopausal women, hormone replacement therapy has been used. However, the results of the randomized trials of the Women's Health Initiative indicated that hormone replacement therapy may not be cardioprotective. The use of mouse models have aided in the understanding of atherosclerosis for many years. These models along with the gender effects attributed to sex hormones are being used to generate a more complete understanding of the development of atherosclerosis. Mice lacking one or both of the genes for estrogen receptors have highlighted the role of estrogen in atherosclerosis. In addition to estrogen, the effects of testosterone have been researched in many animal models and several mechanisms incorporating its role in cholesterol homeostasis have emerged. Our understanding of the pathways involved in gender effects on cardiovascular disease is incomplete, however, a plethora of animal models offer the opportunity to dissect the molecular mechanisms involved.