Measurement of testosterone in the diagnosis of hypogonadism in the ageing male

Many males in their old age demonstrate symptoms consistent with hypogonadism. With the introduction of new and more convenient methods of testosterone replacement treatment of these males is more practical. The diagnosis of hypogonadism in the older male has been controversial with some clinicians suggesting that symptoms should be treated without due reliance on testosterone concentrations. However, most professional bodies have proposed that a low testosterone concentration should be part of the diagnosis. This is, in turn, reliant on the testosterone measurement being reliable and read against an appropriate reference range. This review looks at the factors that can influence the interpretation of testosterone results for the ageing male.     

Treatment of male hypogonadism with testosterone enanthate

To determine the relative efficacy of several dosage regimens of testosterone enanthate in the treatment of male hypogonadism, we treated men who had primary hypogonadism with the following dosage regimens: 100 mg once a week, 200 mg every 2 weeks, 300 mg every 3 weeks, and 400 mg every 4 weeks, each for 12--16 weeks. Twenty-three men completed 37 dosage regimens. The 100-, 200-, and 300-mg dosages all suppressed the initially elevated serum LH concentrations to normal, but the 400-mg dosage did not. The 100- and 200-mg regimens suppressed the initially elevated serum FSH concentrations to normal, and the 300-mg regimen almost did not so. All four regimens produced serum testosterone concentrations that fluctuated largely within the normal range, the average concentration between doses was highest with 100 mg and lowest with 400 mg. The regimens of 200 mg every 2 weeks and 300 mg every 3 weeks appeared to be the most effective of those tested in terms of suppression of the serum LH concentration to normal and infrequency of administration. The close parallel of the FSH response to that of LH suggests that testosterone is the major physiological inhibitor of FSH as well as of LH.     

Transdermal testosterone therapy in the treatment of male hypogonadism

Five hypogonadal men were treated with transdermal testosterone therapy, using a testosterone patch applied to the scrotal skin. Daily application of the patch, which contained 10 mg testosterone, produced an increase in serum testosterone concentrations from a pretreatment value of 45 +/- 12 (+/- SE; 1.5 +/- 0.4) to 436 +/- 80 ng/dL (15.1 +/- 2.8 nmol/L; P less than 0.001) after 4 weeks of treatment. Normal serum testosterone concentrations were achieved in all men after 6-8 weeks of therapy and were maintained during continued long term therapy for 9-12 months with a patch containing 15 mg testosterone. All men reported a subjective increase in libido and sexual function during therapy, and three men preferred it to testosterone injections. The serum testosterone and estradiol levels did not rise above the normal adult male range at any time during therapy. However, elevated serum dihydrotestosterone (DHT) concentrations occurred during treatment; the pretreatment DHT concentration was 95 +/- 3 ng/dL (3.3 +/- 0.1 nmol/L), and it increased to 228 +/- 40 ng/dL (7.8 +/- 1.4 nmol/L) after 4 weeks of treatment and remained elevated thereafter. The individual mean DHT to testosterone ratio increased from a pretreatment value of 0.2 (range, 0.1-0.3) to 0.6 (range, 0.4-0.7) after 2 weeks of therapy and remained high thereafter. Comparison of the serum DHT levels in patients during therapy with those in normal men who had similar testosterone concentrations [531 +/- 62 vs. 566 +/- 72 ng/dL (18.4 +/- 2.1 vs. 19.6 +/- 2.5 nmol/L); P greater than 0.05] revealed that the mean serum DHT concentration was significantly higher in the patients [315 +/- 69 vs. 87 +/- 6 ng/dL (10.8 +/- 2.4 vs. 2.9 +/- 0.2 nmol/L); P less than 0.001], as was the mean DHT to testosterone ratio [0.6 (range, 0.25- 1.1) vs. 0.16 (range, 0.09- 0.24); P less than 0.001]. The high serum DHT levels presumably were due to increased metabolism of testosterone to DHT by the 5 alpha-reductase in the scrotal skin. Serum 3 alpha-androstanediol glucuronide levels were not elevated in the patients. We conclude that transdermal testosterone therapy is an effective long term treatment for hypogonadism in men. It is, however, associated with high serum DHT levels, whose potential long term effects on the prostate and other tissues need to be investigated.     

Clinical practice update on testosterone therapy for male hypogonadism: Contrasting perspectives to optimize care

US Endocrine Society (ES) published a clinical practice guideline on testosterone therapy in men with hypogonadism, and Endocrine Society of Australia (ESA) a position statement on management of male hypogonadism. Both emphasize the importance of diagnosing men who are androgen deficient due to organic (classical or pathological) hypogonadism arising from disorders of the hypothalamus, pituitary or testes, who assuredly benefit from testosterone therapy. Both recognize that men with an intact gonadal axis may have low testosterone concentrations, for instance older men or men with obesity or other medical comorbidities. ES guidelines classify such symptomatic men as having organic (advanced age) or functional (obesity, medical comorbidities) hypogonadism, giving an option for testosterone therapy as a shared decision between clinicians and individual patients. ESA did not recommend testosterone therapy in these men. ES offers a reference range for total testosterone established in young men, while ESA cites age‐standardized reference ranges. ES recommends using free testosterone as well as total testosterone to identify men with hypogonadism in conditions where sex hormone‐binding globulin (SHBG) is altered, or when total testosterone is borderline. ESA recommends confirmatory biochemical testing with total testosterone, recognizing that this may be lower than expected if SHBG concentrations are low. Both emphasize the importance of identifying pre‐existing prostate and cardiovascular disease prior to initiating testosterone therapy, with ES providing specific recommendations for PSA measurement, deferring testosterone therapy after major cardiovascular events and indications for pituitary imaging. These contrasting approaches highlight gaps in the evidence base where individualized patient management is required.     

Intramuscular injection of testosterone undecanoate for the treatment of male hypogonadism: phase I studies

OBJECTIVE: In the search for long-acting testosterone preparations suited for substitution therapy of hypogonadal men, testosterone undecanoate (TU) dissolved in either tea seed oil or castor oil was investigated. DESIGN: In study I, 1000 mg TU in tea seed oil (125 mg/ml) were injected in equal parts into the gluteal muscles of seven hypogonadal men. In study II, 1000 mg TU in castor oil (250 mg/ml) were injected into one gluteal muscle of 14 patients. RESULTS: In comparison with published data on testosterone enanthate, most widely used for i.m. injections, the kinetic profiles of both TU preparations showed extended half-lives and serum levels not exceeding the upper limit of normal. The castor oil preparation had a longer half-life than TU in tea seed oil (33.9+/-4.9 vs 20.9+/-6.0 days (mean pm S.E.M.)). CONCLUSION: The longer half-life and the smaller injection volume make TU in castor oil a strong candidate for further applications in substitution therapy and in trials for male contraception.     

Optimal testosterone level to improve symptoms of hypogonadism without causing dopa-testotoxicosis in male macroprolactinoma

BackgroundMale prolactinoma treatment by dopamine agonists (DA) restores sexual function. However, excessive DA dose can lead to impulse control disorder.ObjectivesThe aim of this retrospective study was to determine the level of testosterone that eliminates symptoms and provides fertility in male macroprolactinoma, without causing these adverse effects.Materials and methodsTwenty-seven male patients with macroprolactinoma were included. There were 16 macro (≥ 1–2.8 cm), 7 large macro (≥ 2.9–3.9 cm) and 4 giant (≥ 4 cm) adenomas. Prolactin (PRL) and testosterone (T) levels were evaluated. A timeline was created to analyze improvement in symptoms of hypogonadism and infertility. Testosterone levels were compared with age-matched controls.ResultsMean PRL, basal tumor diameter and shrinkage were 2846 ± 3415 ng/mL, 27.2 ± 10.2 mm and 63.4%, respectively. Basal T levels were 1.6 ± 1.0 ng/mL for patients and 4.4 ± 1.5 ng/mL for controls (P < 0.001). Mean T level in the asymptomatic period was significantly lower than in controls (3.2 ± 0.4 ng/mL vs. 4.4 ± 1.5 ng/mL, respectively; P = 0.002), while mean PRL was 27.2 ng/mL. Fertility was achieved in 6 of the patients seeking fertility, and there was no difference in T level between these patients and controls (3.7 ± 0.8 ng/mL and 4.4 ± 1.5 ng/mL, respectively; P = 0.14); when fertility was achieved, mean PRL was 26.9 ± 23 ng/mL.ConclusionPatients should be carefully questioned regarding complaints at each consultation, and DA dose should not be increased unnecessarily, to avoid possible serious adverse effects.     

The relationship between plasma prolactin and testosterone levels in male hypogonadism

Fifty seven male patients either complaining of poor sexual development, gynecomastia or dwarfism and signs of sexual infantilism were studied. Plasma prolactin (PRL) and testosterone (T) were estimated in all patients while 33 of them were also subjected to full pituitary function tests. Twelve of the latter had an elevated basal plasma cortisol or growth hormone which suggested the patient may have been "stressed"; the results were analyzed both excluding and including these patients. The remaining patients were divided into those with a plasma T less than 8.0 nmol/l (Group A, 25 patients) and those with a plasma T greater than 8.0 nmol/l (Group B, 20 patients). The results were compared with those from 18 normal men (Group C). The mean plasma PRL in group A (108.1 mU/l) was significantly lower than that in group B (181.5 mU/l, p less than 0.005) or group C (255.7 mU/l, p less than 0.001). The difference between groups A and B became much less (p less than 0.01) when results from the "stressed" patients were included but this did not affect the difference with group C. The mean plasma PRL in group B was also significantly lower (p less than 0.05) than that in group C but the significance of the difference disappeared when all the patients were included (p less than 0.2). In the patients there was a significant correlation between plasma and PRL plasma T (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Salivary cortisol measurement--a reliable method for the diagnosis of Cushing's syndrome.

The measurement of cortisol in saliva is becoming more widely accepted as a screening test for the diagnosis of hypercortisolism. Since 1986, cortisol measurement in saliva has been continuously used in our department. In this study we compared salivary cortisol profiles from proven Cushing's disease patients with profiles from healthy subjects and obese children. The purpose was to evaluate the predictive value of the method for the diagnosis of hypercortisolism and to define cut-off levels to exclude or identify hypercortisolism. Cortisol in saliva was measured in 150 Cushing's disease patients (30 children, 120 adults, ranging from age 4-70), 100 healthy subjects (55 children, 45 adults, ranging from age 6-60), and 31 children (age 7-15) with an age-related body-mass-index above the 90th percentile. Generally, five saliva samples were taken over the day at 6:00-8:00 a.m., 11:00-12:00 a.m., 4:00-6:00 p.m., 7:00-8:00 p.m., and 10:00 p.m. The samples were measured using a radioimmuno-assay (INCSTAR Corporation, Stillwater, Minnesota, USA). For healthy subjects, morning levels of cortisol in saliva between 3-19 microg/l were found. These levels dropped to levels in between <1-11 microg/l at 11:00-12:00 a.m., <1-6 microg/l at 4:00-6:00 p.m., <1-4.5 microg/l at 7:00-8:00 p.m., and <1-2.9 microg/l at 10:00 p.m. The measured values showed a correlation with age, height, and weight. In Cushing's disease patients, the circadian salivary cortisol rhythm was missing, compared to healthy subjects. There was no significant difference in salivary cortisol levels or circadian rhythm between healthy or obese children. We found a high sensitivity for the detection of hypercortisolism at the 10:00 p.m. salivary cortisol measurement. The following, age dependent cut-off levels for salivary cortisol at 10:00 p.m. were calculated for the exclusion of hypercortisolism. Age 6-10: 1.0 microg/l (specificity 100%, sensitivity 87.5%); age 11-15: 1.7 microg/l (specificity 100%, sensitivity 100%); age 16-20: 1.6 microg/l (specificity 100%, sensitivity 76.2%); age 21-60: 1.6 microg/l (specificity 100%, sensitivity 90.9%) [corrected] For the proof of Cushing's syndrome, the following age-dependent cut-off levels at 10:00 p.m. were found: age 6-10: 1.9 microg/l (specificity 100%, sensitivity 80%); age 11-15: 1.7 microg/l (specificity 100%, sensitivity 100%); age 16-20: 2.5 microg/l (specificity 100%, sensitivity 84.2%); age 21-60: 1.9 microg/l (specificity 100%, sensitivity 97.6 %) [corrected] The cortisol assessment in saliva is a sensitive and reliable method to discriminate normocortisolemic from hypercortisolemic patients. From our view, the major advantages of this method are the reliability, non-invasiveness, and use in ambulatory patients.     

Therapy of male hypogonadism

One of the most frequent, but also most undiagnosed, endocrinopathies is male hypogonadism (testosterone deficiency). Understanding the variety of clinical pictures male hypogonadism exhibits is pivotal for diagnosis and putative treatment. There can be disturbances of mood and cognitive abilities as well as sexual functions. Further on, a decrease in muscle mass and strength, an accumulation of body fat and osteopenia/osteoporosis as well as anemia might be observed. There are indications that insulin sensitivity is mitigated in a state of androgen depletion, especially due to an inverse association of testosterone to the metabolic syndrome. In older men, symptoms of androgen deficiency may feature a differential profile due to accompanying co-morbidities. Restoring serum testosterone levels by substitution therapy can markedly attenuate, if not relieve, the clinical picture of hypogonadism. New treatment modalities have been introduced, including short-acting transdermal as well as long-acting depot preparations. Herewith, the diagnostic pathways to describe or exclude male hypogonadism and as well as various options of initiation and surveillance of testosterone substitution therapy are elucidated. Future perspectives of andrology regarding metabolic and pharmacogenetic aspects are discussed.     

New perspectives in the diagnosis of pediatric male hypogonadism: the importance of AMH as a Sertoli cell marker

Sertoli cells are the most active cell population in the testis during infancy and childhood. In these periods of life, hypogonadism can only be evidenced without stimulation tests, if Sertoli cell function is assessed. AMH is a useful marker of prepubertal Sertoli cell activity and number. Serum AMH is high from fetal life until mid-puberty. Testicular AMH production increases in response to FSH and is potently inhibited by androgens. Serum AMH is undetectable in anorchidic patients. In primary or central hypogonadism affecting the whole gonad and established in fetal life or childhood, serum AMH is low. Conversely, when hypogonadism affects only Leydig cells (e.g. LHβ mutations, LH/CG receptor or steroidogenic enzyme defects), serum AMH is normal or high. In pubertal males with central hypogonadism, AMH is low for Tanner stage (reflecting lack of FSH stimulus), but high for the age (indicating lack of testosterone inhibitory effect). Treatment with FSH provokes an increase in serum AMH, whereas hCG administration increases testosterone levels, which downregulate AMH. In conclusion, assessment of serum AMH is helpful to evaluate gonadal function, without the need for stimulation tests, and guides etiological diagnosis of pediatric male hypogonadism. Furthermore, serum AMH is an excellent marker of FSH and androgen action on the testis.     

Obesity and male hypogonadism: Tales of a vicious cycle

Obesity prevalence, particularly in children and young adults, is perilously increasing worldwide foreseeing serious negative health impacts in the future to come. Obesity is linked to impaired male gonadal function and is currently a major cause of hypogonadism. Besides signs and symptoms directly derived from decreased circulating testosterone levels, males with obesity also present poor fertility outcomes, further evidencing the parallelism between obesity and male reproductive function. In addition, males with androgen deficiency also exhibit increased fat accumulation and reduced muscle and mineral bone mass. Thus, compelling evidence highlights a vicious cycle where male hypogonadism can lead to increased adiposity, while obesity can be a cause for male hypogonadism. On the opposite direction, sustained weight loss can attain amelioration of male gonadal function. In this scenario, a thorough evaluation of gonadal function in men with obesity is crucial to dissect the causes from the consequences in order to target clinical interventions towards maximized improvement of reproductive health. This review will address the causes and consequences of the bidirectional relationship between obesity and hypogonadism, highlighting the implicit male reproductive repercussions.     

Approach to the male patient with congenital hypogonadotropic hypogonadism

The term "congenital hypogonadotropic hypogonadism" (CHH) refers to a group of disorders featuring complete or partial pubertal failure due to insufficient secretion of the pituitary gonadotropins LH and FSH. Many boys (or their parents) will seek medical consultation because of partial or absent virilization after 14 yr of age. Small testes are very frequent, but height is generally normal. Laboratory diagnosis of hypogonadotropic hypogonadism is relatively simple, with very low circulating total testosterone and low to low-normal gonadotropin and inhibin B levels. This hormone profile rules out a primary testicular disorder. Before diagnosing CHH, however, it is necessary to rule out a pituitary tumor or pituitary infiltration by imaging studies, juvenile hemochromatosis, and a systemic disorder that, by undermining nutritional status, could affect gonadotropin secretion and pubertal development. Anterior pituitary function must be thoroughly investigated to rule out a more complex endocrine disorder with multiple hormone deficiencies and thus to conclude that the hypogonadotropic hypogonadism is isolated. The most likely differential diagnosis before age 18 yr is constitutional delay of puberty. Apart from non-Kallmann syndromic forms, which are often diagnosed during childhood, the two main forms of CHH seen by endocrinologists are Kallmann syndrome, in which CHH is associated with impaired sense of smell, and isolated CHH with normal olfaction. Anosmia can be easily diagnosed by questioning the patient, whereas olfactometry is necessary to determine reliably whether olfaction is normal or partially defective. This step is important before embarking on a search for genetic mutations, which will also be useful for genetic counseling. The choice of a particular hormone replacement therapy protocol aimed at virilizing the patient will depend on age at diagnosis and local practices.     

Bone mineral density outcomes following long-term treatment with subcutaneous testosterone pellet implants in male hypogonadism

BACKGROUND: Osteoporosis is a common complication of untreated male hypogonadism. Even mild hypogonadism due to suboptimal testosterone replacement may result in decreased bone mineralization and osteoporosis. OBJECTIVE: To assess bone mineral density in hypogonadal men following long-term long-acting subcutaneous testosterone pellet implants as replacement therapy. PATIENTS: A cross-sectional study of 37 patients with primary or secondary hypogonadism receiving long-term (mean 6.6 years) subcutaneous testosterone pellet implants as replacement therapy. MEASUREMENTS: Bone mineral density was measured in all patients using dual energy X-ray absorptiometry. Serum testosterone 3-4 months after insertion of pellets was measured in all patients to assess adequacy of replacement therapy. RESULTS: Mean areal bone mineral density were 1.02 (SD 0.14) g/cm2 with a mean Z score of -0.64 (SD 1.3) and 0.87 (SD 0.13) g/cm2 with a mean Z score of -0.72 (SD 1.2) at lumbar spine and neck of femur, respectively. Mean serum testosterone 3-4 months after pellets insertion was 15.45 nmol/l (SD 4.2 nmol/l). There was no significant correlation between bone mineral density and patient's age at start or duration of testosterone therapy. CONCLUSIONS: Bone mineral density in long-term regularly treated hypogonadal men was not different from the age-matched reference range for normal men. Long-acting subcutaneous testosterone pellet implants as replacement therapy in male hypogonadism are safe, acceptable to the patient, result in adequate bone mass accumulation and maintenance of normal bone mineral density. By provision of sustained physiological levels of testosterone they may contribute to increased androgen effect at the receptor level.     

Testosterone depot injection in male hypogonadism: a critical appraisal

Testosterone compounds have been available for almost 70 years, but the pharmaceutical formulations have been less than ideal. Traditionally, injectable testosterone esters have been used for treatment, but they generate supranormal testosterone levels shortly after the 2- to 3-weekly injection interval and then testosterone levels decline very rapidly, becoming subnormal in the days before the next injection. The rapid fluctuations in plasma testosterone are subjectively experienced as disagreeable. Testosterone undecanoate is a new injectable testosterone preparation with a considerably better pharmacokinetic profile. After 2 initial injections with a 6-week interval, the following intervals between two injections are almost always 12-weeks, amounting eventually to a total of 4 injections per year. Plasma testosterone levels with this preparation are nearly always in the range of normal men, so are its metabolic products estradiol and dihydrotestosterone. The “roller coaster” effects of traditional parenteral testosterone injections are not apparent. It reverses the effects of hypogonadism on bone and muscle and metabolic parameters and on sexual functions. Its safety profile is excellent due to the continuous normalcy of plasma testosterone levels. No polycythemia has been observed, and no adverse effects on lipid profiles. Prostate safety parameters are well within reference limits. There was no impairment of uroflow. Testosterone undecanoate is a valuable contribution to the treatment options of androgen deficiency.