Treatment Of Hypogonadism Research Articles

Selective Androgen Receptor Modulators in Drug Discovery: Medicinal Chemistry and Therapeutic Potential

Modulation of the androgen receptor has the potential to be an effective treatment for hypogonadism, andropause, and associated conditions such as sarcopenia, osteoporosis, benign prostatic hyperplasia, and sexual dysfunction. Side effects associated with classical anabolic steroid treatments have driven the quest for drugs that demonstrate improved therapeutic profiles. Novel, non-steroidal compounds that show tissue selective activity and improved pharmacokinetic properties have been developed. This review provides an overview of current advances in the development of selective androgen receptor modulators (SARMs).

Clinical course of congenital nephrotic syndrome and Denys‐Drash syndrome in Japan

The prognosis of Japanese patients with congenital nephrotic syndrome (CNS) and Denys-Drash syndrome (DDS) is not clear. Five patients with CNS and four patients with DDS, which causes secondary CNS, were studied retrospectively. Seven patients were sporadic and two DDS patients were identical twins. Five CNS patients presented with edema within 3 months of birth. In four DDS patients, edema was not noted and end-stage renal disease developed between 7 months and 6 years of age. Of these five CNS patients, one patient had cerebral thrombosis and cytomegalovirus pneumonia at the onset and another patient died during dialysis. Frequent intravenous albumin administration required, growth and development during infancy were varied. Of the nine patients with CNS and DDS, seven received renal transplantation and were alive with functioning grafts at the last follow up. Catch-up growth was observed in five patients after transplantation. Five school-aged patients attended school and received adequate grades and two adults worked full-time. Of the DDS patients, dysuria due to hypospadias persisted in one patient and treatment for hypogonadism was needed in one patient. CNS and DDS were diagnosed early after onset and adequate treatment was started. Growth and development after renal transplantation were relatively good. Thrombotic episodes or severe infection in CNS patients was difficult to manage and complications resulting from DDS affected the quality of life.

Clomiphene Citrate Effects on Testosterone/Estrogen Ratio in Male Hypogonadism

Symptomatic late-onset hypogonadism is associated not only with a decline in serum testosterone, but also with a rise in serum estradiol. These endocrine changes negatively affect libido, sexual function, mood, behavior, lean body mass, and bone density. Currently, the most common treatment is exogenous testosterone therapy. This treatment can be associated with skin irritation, gynecomastia, nipple tenderness, testicular atrophy, and decline in sperm counts. In this study we investigated the efficacy of clomiphene citrate in the treatment of hypogonadism with the objectives of raising endogenous serum testosterone (T) and improving the testosterone/estrogen (T/E) ratio. Our cohort consisted of 36 Caucasian men with hypogonadism defined as serum testosterone level less than 300 ng/dL. Each patient was treated with a daily dose of 25 mg clomiphene citrate and followed prospectively. Analysis of baseline and follow-up serum levels of testosterone and estradiol levels were performed. The mean age was 39 years, and the mean pretreatment testosterone and estrogen levels were 247.6 +/- 39.8 ng/dL and 32.3 +/- 10.9, respectively. By the first follow-up visit (4-6 weeks), the mean testosterone level rose to 610.0 +/- 178.6 ng/dL (P < 0.00001). Moreover, the T/E ratio improved from 8.7 to 14.2 (P < 0.001). There were no side effects reported by the patients. Low dose clomiphene citrate is effective in elevating serum testosterone levels and improving the testosterone/estradiol ratio in men with hypogonadism. This therapy represents an alternative to testosterone therapy by stimulating the endogenous androgen production pathway.

Anabolic Steroid-Associated Infertility: A Potentially Treatable and Reversible Cause of Male Infertility

Anabolic steroid abuse has become a major public health problem around the world. Olympic athletes, professional athletes, college and high school students utilize these drugs for their muscle and strength building benefits. However, the short and long term effects on reproductive and sexual function have not been reported in a series of patients. Pharmacologic doses of testosterone-based drugs cause drops in endogenous testosterone production and result in impairment of spermatogenesis. Classically, patients actively taking anabolic steroids present with severe oligospermia or azoospermia, with a suppressed hypothalamic-pituitary axis. The objective of this study is to evaluate the clinical characteristics and outcomes of male infertility patients with a history of anabolic steroid abuse. Retrospective chart review of infertility patients with history of anabolic steroid abuse from a single male infertility clinic. Chart review was performed on patients from one infertility clinic from 1995-2005. All patients with a history of illicit anabolic steroid use at the present time or in the past were included. Data collection was performed regarding patient age, temporal relationship to steroid abuse, semen parameters, hormonal parameters and subsequent treatment and outcome if available. Patients were excluded if they were prescribed testosterone from other physicians for “treatment of hypogonadism.” A review of charts in patients presenting to a single infertility clinic revealed 15 patients with a clear reportable history of self-administered anabolic steroid abuse. The average patient age was 33 yrs. The average number of years since anabolic steroid use was 5.3 yrs[range: actively using (5 patients) to 19 years prior to presentation]. The average number of cycles of anabolic steroids utilized ranged from one to many years of continuous anabolic steroid use. 11/15 pts presented with typical low testosterone, low follicle stimulating hormone and low luteinizing hormone levels. Of the other 4 patients, one had non-obstructive azoospermia, one had an epididymal obstruction, one had a vasectomy with testis biopsy showing diminished spermatogenesis and one had vasal atresia with normal hormonal parameters. Of classic anabolic patients, 81% (9/11) of patients were azoospermic, 19% (2/11) of patients were mildly or moderately oligospermic and 55% (6/11) of patients had history of prior paternity. Azoospermia was reversible with either cessation of anabolic steroids or gonadotropin replacement in 78% (7/9) of patients. 71% (5/7) of patients required gonadotropin therapy for return of spermatogenesis and 29% (2/7) of patients had spontaneous return of spermatogenesis after cessation of anabolic steroids. Anabolic steroid-associated infertility typically follows a pattern of hypogonadotropic hypogonadism that usually results in azoospermia. Not all patients with a history of anabolic steroid abuse are infertile and these data do not allow global conclusions to be drawn regarding all patients who have abused anabolic steroids. Treatment is available for infertile patients who have abused anabolic steroids, which includes rebound spermatogenesis with cessation of drugs, treatment with gonadotropins or possibly testis sperm retrieval/ICSI.

Advances in male hormone substitution therapy

Increased awareness of the clinical diagnosis of male hypogonadism has resulted in the wider use of androgen substitution therapy. Clinical signs and symptoms together with a low serum testosterone level confirm the diagnosis of male hypogonadism. Androgen replacement results in improved sexual function, mood, muscle mass and bone density in most hypogonadal men. Such benefits must be assessed against potential risks. In older men, the potential risks of androgen treatment of hypogonadism are not known. Many delivery systems for androgen substitution are now available; the preparation chosen depends on the choice of the patient and his physician. Selective androgen receptor modulators offer tissue selective biological effects and the possibility of attaining maximum efficacy and minimum adverse effects.

OUTCOME OF GONADOTROPIN THERAPY FOR MALE HYPOGONADOTROPIC HYPOGONADISM AT UNIVERSITY AFFILIATED MALE INFERTILITY CENTERS: A 30-YEAR RETROSPECTIVE STUDY

Hypogonadotropic hypogonadism (HH) is an uncommon cause of male infertility. Even specialized centers see small numbers of patients and have little experience in restoring fertility in these patients. To explore the phenotypic heterogeneity and treatment outcome of HH, we summarized our 30-year experience. Medical charts of 36 male patients (age range 11 to 42 years) with HH (81% primary, 19% secondary) treated at university affiliated male infertility centers were reviewed. Pubic hair stage, genital stage, testicular volume (TV), sexual function and sperm production were determined before and after human chorionic gonadotropin/human menopausal gonadotropin (hCG/hMG) treatment. Differences were analyzed statistically. The population was stratified according to initial TV into a small testis subset (TV less than 4 ml in 23) and a large testis subset (TV 4 ml or greater in 13). Comparison of these 2 subsets revealed significant differences in the incidence of cryptorchidism (39% vs 8%) and Kallmann's syndrome (22% vs 0%), pubic hair stage (1.3 +/- 0.5 vs 3.5 +/- 1.4), genital stage (1.2 +/- 0.4 vs 3.9 +/- 0.9) and TV (1.6 +/- 0.9 vs 7.5 +/- 3.5 ml). Long-term administration of hCG/hMG for 12 to 240 months (average 56 +/- 11) resulted in sperm production in only 36% of the small testis subjects but in 71% of the large testis subjects. Initial TV values provide insight into phenotypic variables such as time of onset and severity in patients with primary or secondary HH, and may predict sperm output in response to hCG/hMG therapy.

Testosterone Substitution and the Prostate

Testosterone substitution is reported to produce a wide range of benefits for men with hypogonadism that include improvements in muscle mass, body composition, mood, bone density, libido, and cognition. Understanding the actions of exogenous testosterone on the prostate gland is important since testosterone is the major regulator of growth and function of this organ. To date, clinical studies of the effects of testosterone substitution on prostate health suggest that testosterone substitution does not exacerbate lower urinary tract symptoms (LUTS) attributable to benign prostatic hyperplasia (BPH), although it may increase prostate volume. The greatest concern associated with testosterone substitution is the possibility of increased risk of prostate cancer. The relationship between prostate cancer and testosterone is not completely understood. While there is currently no compelling evidence that the use of testosterone substitution in men with hypogonadism increases the risk of prostate cancer, close monitoring of the levels of testosterone and prostate-specific antigen (PSA) along with regular digital rectal examination (DRE) are advised to detect early signs of prostate cancer in subjects receiving long-term testosterone substitution. This review considers the physiological and pharmacological actions of testosterone on the prostate gland, and the risks of BPH and prostate cancer in ageing males receiving testosterone substitution for the treatment of hypogonadism.

Effect of aromatase inhibition on bone metabolism in elderly hypogonadal men

Both estrogens and androgens play important roles in skeletal development and maintenance in men. The relative importance of estrogens and androgens in male bone metabolism, however, remains undefined. Anastrozole is an oral aromatase inhibitor that decreases estrogen production and increases androgen production in men. Currently, anastrozole is being investigated as a potential agent for the treatment of hypogonadism in aging men. Because anastrozole lowers estrogen levels and raises androgen levels, its effect on bone metabolism is difficult to predict. To assess the effects of anastrozole on bone turnover, we randomized 37 elderly (ages 62-74) mildly hypogonadal men (serum testosterone <350 ng/dl) to receive either anastrozole 1 mg daily (n=12), anastrozole 1 mg twice weekly (n=11), or daily placebo (n=14) for 12 weeks. Serum gonadal steroid levels, serum and urine biochemical markers of bone turnover, serum osteoprotegerin, and total body bone mineral density were measured at baseline and week 12. Mean serum levels of total and bioavailable testosterone increased substantially in both treated groups. Specifically, mean +/- SD bioavailable testosterone levels increased from 99+/-31 ng/dl to 207+/-65 ng/dl in the group receiving 1 mg of anastrozole daily and from 115+/-37 ng/dl to 178+/-55 ng/dl in the subjects receiving 1 mg of anastrozole twice weekly ( p <0.001 vs placebo for both groups). Serum estradiol levels decreased modestly in both treated groups (from 26+/-8 pg/ml to 17+/-6 pg/ml in the daily treatment group and from 27+/-8 pg/ml to 17+/-5 pg/ml in the twice-weekly treatment group, p <0.001 vs placebo for both groups). Despite these hormonal changes, no increases in biochemical markers of bone resorption were observed. Specifically, mean serum N-telopeptide and urinary deoxypyridinoline concentrations remained stable in both treated groups over the 12-week treatment period. Similarly, serum biochemical markers of bone formation (osteocalcin and amino-terminal propeptide of type 1 collagen), serum osteoprotegerin, and total body bone mineral density did not change. These data demonstrate that although short-term administration of anastrozole decreases serum estradiol levels in elderly men with mild hypogonadism, this intervention does not adversely affect bone metabolism over a 12-week period. This lack of an effect may be due to the concomitant increase in testosterone production, the relative modest effect on estradiol production, or a combination of both factors. These results suggest that anastrozole therapy is unlikely to have an adverse effect on bone metabolism when taken over extended periods and may prove to be a valuable method of normalizing testosterone production in older men.

Treatment of hypogonadism in men with chronic kidney disease

Hypogonadism is common among men with chronic kidney disease, but few studies have directly assessed the effects of testosterone replacement in this population. Limited information suggests that androgen replacement may improve libido and sexual function among men who are frankly hypogonadal. However, the threshold for normal sexual function is in the lower end of the normal range. Increasing serum testosterone above this level does not appear to have beneficial effects on sexual functioning. On the other hand, at least among healthy men, the dose-response curve for anabolic effects of testosterone administration appears to extend to testosterone levels on the high end of the normal range or above. Small studies have suggested that androgen treatment has anabolic effects among end-stage renal disease patients, even in the absence of hypogonadism. Androgens have potential side effects, and some preinitiation and subsequent assessment and monitoring are recommended to minimize these adverse effects. Recommendations for healthy older men appear to be reasonable for patients with chronic kidney disease. More research is needed to measure the effects of androgen therapy on various symptoms of hypogonadism as well as on overall quality of life, physical functioning, and survival among patients with chronic kidney disease.

Treatment of hypogonadism in men with chronic kidney disease

Treatment of hypogonadism in men with chronic kidney disease

Organic, relational and psychological factors in erectile dysfunction in men with diabetes mellitus.

Diabetes mellitus-induced erectile dysfunction (DMED) is thought to be multifactorial in aetiology and to include vascular, neurological, and psychological components. The aim of the present study is to determine the contribution of organic, relational, and intrapsychic components to the pathogenesis of ED in diabetic in comparison with non-diabetic patients. We studied a consecutive series of 1027 using SIEDY structured interview. A complete physical examination and a series of metabolic, biochemical, hormonal, psychometric, penile vascular tests and nocturnal penile tumescence and rigidity evaluations were performed. 15% of patient studied were affected by DMED. Diabetic patients with DMED have a greater severity of erectile dysfunction and are more likely to have an organic, rather than an intrapsychic, component. Impaired sexual desire is less frequent in these patients and they had an higher prevalence of hypogonadism than non-diabetic individuals. Diabetic patients seeking treatment for erectile dysfunction have a greater severity of disease, less impaired sexual desire, suggesting that the need for medical care in diabetic patients with ED could be even greater than in their non-diabetic counterparts. Considering the higher prevalence of obesity-related decrease of testosterone levels in DMED, an appropriate screening and treatment of hypogonadism might improve the outcome of pharmacotherapy for ED in diabetic patients.

Testosterone Undecanoate ??? Schering AG

Schering AG is developing a formulation of testosterone undecanoate [Nebido] for the treatment of testosterone deficiency or hypogonadism. This deficiency can lead to decreased muscle mass, impaired muscle function, osteoporosis, reduced sexual function and mental degeneration. Schering claims that its new formulation provides superior control of blood levels of the drug and permits a longer period of application. Nebido requires only four injections per year, and represents a major improvement for men with testosterone deficiency. Schering AG received approval of its testosterone undecanoate formulation in its first European country, Finland, in November 2003 for the treatment of hypogonadism in men. In July 2004, Schering's testosterone undecanoate formulation completed approval of the European mutual recognition procedure. This approval clears the way for marketing the product (as Nebido) in the large pharmaceutical markets like Germany, France and the UK. The initial phase of the product launch will occur in Finland in October 2004, and in Germany in November 2004. Other European countries will follow in 2005, and following receipt of approval, it will be introduced in the first Latin American and Asian countries. In its 2002 Annual Report, Schering predicted that testosterone undecanoate has the potential to reach peak sales of euro 100 million, 3 years after launch-launch in Europe was at the time anticipated in 2004.

Hypogonadism and erectile dysfunction: pathophysiological observations and therapeutic outcomes.

Androgens have a profound effect in male sexual function in general and erectile physiology in particular. Despite the common belief that male sexuality is fully dependent on normal androgens, hypogonadal men are capable of sexual erections; almost a third of men receiving effective antiandrogen therapy can develop erections when tested with an erotic challenge. However, successful hormonal supplementation that results in normal testosterone values does not always restore libido and erectile function. Although the primary goal of treatment for hypogonadism may be to restore sexual function, there will be other significant benefits and potential drawbacks. Libido, general well-being, osteoporosis, muscle strength, mental acuity, and growth hormone levels will all be positively affected by appropriate management of low testosterone levels. Testosterone replacement therapy should maintain not only physiological levels of serum testosterone but also its metabolites, including dihydrotestosterone and oestradiol. The assessment of hypogonadism, its treatment and monitoring, are unavoidable responsibilities of the urologist.

Diagnosis and Treatment of Hypogonadism With Emphasis on Erectile Dysfunction and Osteoporosis

Diagnosis and Treatment of Hypogonadism With Emphasis on Erectile Dysfunction and Osteoporosis

American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Evaluation and Treatment of Hypogonadism in Adult Male Patients—2002 Update

In these clinical practice guidelines, specific recommendations are made for determining the most effective methods of diagnosing and treating hypogonadism in adult male patients. The target populations for these guidelines include the following: (1) men with primary testicular failure requiring testosterone replacement (hypergonadotropic hypogonadism); (2) male patients with gonadotropin deficiency or dysfunction who may have received testosterone replacement therapy or treatment for infertility (hypogonadotropic hypogonadism); and (3) aging men with symptoms relating to testosterone deficiency who could benefit from testosterone replacement therapy. Initial hormonal evaluation generally consists of a testosterone determination, in conjunction with a free testosterone or sex hormone-binding globulin level, inpatients with clear symptoms and signs but normal-range total testosterone, follicle-stimulating hormone, luteinizing hormone, and prolactin levels. Other possible tests include semen analysis, pituitary imaging studies, genetic studies, bone densitometry, testicular ultrasonography,testicular biopsy, and specialized hormonal dynamic testing. Therapeutic options generally consist of testosterone replacement by injections, patches, or topically applied gel in hypergonadotropic patients and in hypogonadotropic patients not interested in fertility. In hypogonadotropic patients interested in fertility, gonadal stimulation option scan be considered, including human chorionic gonadotropin stimulation therapy with or without human menopausal gonadotropin (or follicle-stimulating hormone) or gonadotropin-releasing hormone pump therapy. These therapies may be combined with assisted reproductive technologies such as in vitro fertilization with intracytoplasmic sperm injection, which may allow pregnancy to occur with very low numbers of sperm.

Osteoporosis in men: are we ready to diagnose and treat?

Because osteoporosis and its attendant fractures are more common in women than in men, most studies have been performed in women. However, age-related osteoporosis and fragility fractures are also a major problem in men. Recent studies suggest that diagnosing men as osteoporotic when they fall more than 2.5 standard deviations below the mean for young men identifies a group at risk for fracture. Data suggest that many men with femoral fractures have age-related hypogonadism. Hypogonadism is associated with decreased lean body mass and bone mass. Most men with femoral fractures are reported to be hypogonadal. Testosterone replacement in hypogonadal older men improves bone mass and lean body mass. A therapeutic intervention to reduce fracture incidence in men with osteoporosis has been reported. No population-based study has examined the incidence or prevalence of hypogonadism with or without osteoporosis in men. Thus, osteoporosis in men probably exists with and without hypogonadism. Therapeutic interventions should be based on treatment of hypogonadism when present with osteoporosis.

IMPAIRED LIBIDO IN HOCKEY PLAYER

HISTORY A 24 year old male hockey player presented to the physician's office with an initial complaint of injured forefinger but it became clear that his main concern was inability to have an erection. This was ongoing for 2 years. Past medical history revealed some vague problems with his liver and patient had declined a liver biopsy. No current medications. Pt admitted to 6 years of anabolic steroid use (since age 16) stopping 2 years ago. Pt. denies problems with hypertension, cardiovascular disease, peripheral vessel disease, diabetes, wt change or trauma to the groin; he reveals recent treatment for a chlamydia infection. PHYSICAL EXAMINATION VITAL SIGNS: BP 120/84 HR 76 wt 188.9 pounds ht 5 feet, 10.5 inches RR 16. GENERAL: Well developed well nourished male with muscular physique. GENITAL: shaven genital area, circumsized, descended testicles, measuring 2.2 to 2.5 cm, soft, large grapelike appearance in size; no hernia; RECTAL: boggy prostate with tenderness. DIFFERENTIAL DIAGNOSIS Impotence related to anabolic steroid use (hypogonadatropic hypogonadism) or trauma, neurologic, vascular or drug etiologies; persistent exogenous steroid use; liver dysfunction; prostatitis. LAB TESTS Urinalysis 3–8 White Blood Cells per high power field; Urine culture no growth; LIVER FUNCTION TESTS: Albumin 4.8 g/dL [3.5–5.0], Prothrombin Time 13.8 sec [11.7–13.5], Alk Phosphatase 107 U/L [38–126], AST (SGOT) 45 U/L [14–41], ALT (SGPT) 46 U/L [17–63]; HEPATITIS SCREEN: negative for HEP B,C, and A; DHEA 619 ng/ml [140–1250], Luteinizing Hormone < 0.5 MIU/ml [2.0–12.0], Prolaction 9.6 ng/ml [1.6–18.8], Total Testosterone 189 ng/dL [270–1194]; Prostate Specific Antigen 1.1 ng/ml [0.0–4.0]. DIAGNOSIS HYPOGONADATROPIC HYPOGONADISM TREATMENT:Chorionic Gonadatropin 2,500 U SQ biweekly with 4 month taper

Characterization Of Patients In A Medical Endocrine-Based Center For Male Sexual Dysfunction

ObjectiveTo characterize the patient population in a multidisciplinary sexual dysfunction clinic whose focal person is an endocrinologist and to summarize the initial manifestations, the demographics of the study group, and their associated medical conditions. MethodsWe undertook a retrospective analysis of the medical records of all new consultations in a center for sexual function during a recent 2-year period. ResultsDuring the period from July 1995 to July 1997, 1,050 men were seen in new consultations for sexual dysfunction at our medical facility, and complete medical records could be retrieved for 990 of them. Of the overall study group of 990 men, most (93.2%) had erectile dysfunction (versus libido or ejaculatory problems), but combinations of problems were common. Most men had organic causes of their sexual dysfunction that correlated with increasing age; however, their dysfunction was more often the result of chronic medical conditions than of advancing age itself. Most men were married (72.1%) and in long-term relationships (mean duration, more than 20 years). Hypogonadism was the most common medical condition (36.3%), a finding that reflected an endocrine referral bias. Testosterone treatment alone corrected the complaints in a minority of patients. Hypertension was a more common diagnosis than diabetes (35.8% versus 23.1%), and pituitary tumors were rare. Successful outcomes were achieved in about two-thirds of men having a strong organic cause of sexual dysfunction, but treatments were less successful when pronounced psychologic factors were present. The patient dropout rate was substantial and was similar in each of the four 6-month quarters—an indication that even as newer therapies became available, dissatisfaction was still evident. ConclusionMany patients have more than one manifestation of sexual dysfunction, which may have to be addressed separately. In a sexual dysfunction clinic managed by an endocrinologist, referral bias may direct more patients with hypogonadism and fewer patients who have had transurethral retropubic prostatectomy or a radical prostatectomy. Treatment of hypogonadism corrects sexual dysfunction in only a few men, and only when other medical problems are not present. Although the percentage of men with diabetes would be expected to be high in this study, the number of patients with hypertension was higher. A considerable dropout rate during evaluation and treatment persisted throughout this study. (Endocr Pract. 1999;5:314-321)

Experience with transdermal testosterone replacement therapy for hypogonadal men

BACKGROUND None of the existing options for long-term testosterone replacement therapy (TRT) for hypogonadal men are ideal. Depot replacement at frequent intervals and implants are effective but invasive and inconvenient for the patient. Oral therapy results in poor hormone levels. Both are associated with undesirable metabolic changes. A transdermal formulation therefore represents a potential therapeutic advance for testosterone replacement. OBJECTIVE To carry out a clinical audit of the acceptability and efficacy as a treatment for hypogonadism of the first transdermal testosterone therapy available in the UK (Andropatch, SmithKline Beecham) compared with existing androgen replacement options. PATIENTS AND MEASUREMENTS Serum testosterone and questionnaire data on treatment efficacy, side-effects, therapy preference, sexual dysfunction and partner's attitudes to therapy were obtained from 50 hypogonadal men prescribed long-term testosterone replacement. RESULTS Eighty per cent of the men returned analysable questionnaires. Eighty-four per cent experienced adverse effects with transdermal therapy, most commonly dermatological problems; 22% of the sample elected to continue with transdermal therapy, 72% returned to depot and 5% returned to oral therapy. The reservoir patches were judged to be too large, uncomfortable, visually obtrusive and noisy. Testosterone levels were comparable to those obtained with depot replacement with the added advantage of a more physiological pharmacokinetic profile. Men taking oral preparations were consistently under-replaced. CONCLUSIONS Adverse events were substantially higher than reported from clinical trials but in keeping with the spectrum of yellow card reports received by the Committee on Safety of Medicines. The pharmacokinetic advantages are thus largely outweighed by low patient acceptability. In its present form transdermal therapy remains an expensive option for those who cannot tolerate depot testosterone replacement.

Transplantation of the testis; from the past to the present.

Since the development of surgery, the possibility of testis transplantation has fascinated man for centuries. Hunter and Berthold are considered to be the most important investigators in this field and, in addition, to be the founders of modern endocrinology. The association of testis transplantation with rejuvenation led to widespread popularity for this treatment in the first three decades of the twentieth century. At the same time, controversies concerning the aim of the treatment have coloured the early years of endocrinology. In the 1960s renewed interest in the subject arose for experimental reasons, leading to the development of microsurgical techniques for autotransplantation of high-lying undescended testes in children. Homologous testis transplantation has never become a subject of great interest, probably for ethical reasons. This possible treatment for hypogonadism, however, has been developed experimentally and has been performed in man only in Russia and China, evidently with success. The details of these studies and their outcomes are discussed.