Contribution de la testostérone biodisponible aux explorations hormonales pour le diagnostic de l’andropause

The measurement of bioavailable testosterone (BT) is considered to be an essential analytical criterion for the diagnosis of male hypogonadism, but the reported normal values differ from one study to another and no consensus has been reached concerning the cut-off values for the diagnosis of androgen deficiency in aging males. Using the lower values measured in a group of clinically normogonadic men between the ages of 40 and 49 years, we have established our own cut-off values: 8 nmol/L for total testosterone and 3.5 nmol/L for BT. By applying these criteria to a group of 87 men with clinical symptoms of androgen deficiency, androgen deficiency was confirmed by laboratory assays in only 14% of these men based on total testosterone, but in 60% of men based on BT. The inverse correlation between BT and SHBG was confirmed regardless of the total testosterone level. SHBG assay is very useful for the diagnosis of androgen deficiency in a population of older males, but cannot replace direct measurement of BT for an accurate individual diagnosis.     

Andropause or Male Menopause? Rationale for Testosterone Replacement Therapy in Older Men with Low Testosterone Levels

ObjectiveTo provide rationale for testosterone replacement therapy (TRT) in older men with low testosterone levels and symptoms consistent with testosterone deficiency.MethodsThe relevant literature was reviewed using PubMedResultsCross-sectional and longitudinal population-based studies indicate that total and free testosterone levels fall with aging, and they may be accompanied by symptoms consistent with androgen deficiency. Testosterone treatment of younger men with very low testosterone levels and hypothalamic, pituitary, or testicular disease is associated with improvements in symptoms, body composition, bone density, and hematocrit/hemoglobin. Studies evaluating testosterone treatment of older men with low testosterone levels are limited, but they suggest some increase in fat free mass, some decrease in fat mass, and some increase in bone density of the lumbar spine and femoral neck.ConclusionThe Testosterone Trial should provide definitive information regarding the potential benefits of TRT in men ≥ years of age. If efficacy is confirmed, we will still need more information regarding the risks of TRT in older men. (Endocr Pract. 2013;19:847-852)     

Réflexion multidisciplinaire sur la prise en charge du Déficit androgénique lié à l’âge

The diagnosis of the androgen deficiency of the aging male (ADAM) is suspected in the presence of relatively unspecific clinical symptoms. The biological evidence of androgen deficiency should be given by using an assay taking into account the level of the sex hormone binding protein (SHBG), such as the bioavailable testosterone assay or, at least, the free testosterone index or the calculated free testosterone which both require measuring total testosterone and SHBG levels. Although the threshold value for defining ADAM has not been fully investigated, the lower limit of normal values in healthy young men which is commonly used for including subjects in therapeutic trials, seems appropriate. According to the currently available data, testosterone replacement therapy in hypogonadal aging men seems to be beneficial to quality of life, sexuality, metabolic status, body composition and osteoporosis. The initiation of androgen replacement therapy requires a careful screening for prostate cancer. Prostate and hematocrit must be monitored during the replacement therapy which is intended for maintaining testosterone levels in the physiological range. Associated disease should be accounted for as a possible factor worsening ADAM and could be relevant of a specific therapy.     

Relations between sex hormone level and characters of hair and skin in healthy young men.

Total testosterone and dihydrotestosterone in blood serum as well as free testosterone in saliva were determined by radioimmunoassay in 110 healthy young men. The results were compared with the development of terminal hair on the trunk and limbs, with the disposition to balding and with the disposition to acne. No significant correlations were found between terminal hair development and absolute androgen levels; however, some significant values were observed in the case of the metabolic rate of dihydrotestosterone/testosterone and the proportion of free to total testosterone. The disposition to balding also correlates positively with the latter ratio. Yet the absolute serum androgen concentrations in men with a disposition to balding is lower than in men with no reduction of scalp hair. The widespread assumption that androgen levels are in general elevated in bald-trait men must therefore be rejected. In accordance with this finding, men with a disposition to balding are morphologically (with regard to anthropometric measures) no more masculine than those with good scalp hair growth. When body build and age are taken into consideration, the relations between terminal hair and androgen ratio are also problematical. No relationship could be found between acne and androgens.     

Helpful diagnostic markers of steroidogenesis for defining hyperandrogenemia in hirsute women

HYPOTHESIS: Androgen excess carries varied clinical manifestations in women. Although testosterone and dehydroepiandrostendionesulfate (DHEAS) determination is considered useful in diagnostic workup, there is no laboratory definition that sufficiently describes androgen excess. DESIGN: We studied 464 hirsute women with a Ferriman and Gallwey score of at least 8 between 2000 and 2005. Our examination included clinical data, total testosterone (T), sex hormone-binding globulin (SHBG), the free androgen index (FAI), and DHEAS. Additionally, androstendione, 17alpha-hydroxyprogesterone (17OHP), dehydroepiandrostendione (DHEA), and 11-deoxycortisol were determined at baseline and 60min after corticotropin challenge (250microg synacthen). RESULTS: Of 464 women, 77.6% fulfilled the clinical criteria for hyperandrogenemia. Of these 360 women, 78.1% had hyperandrogenic hirsutism. Of these 281 women, 43.4% showed increased stimulation of 17OHP to 250microg of synacthen. Another 37.4% showed adrenal steroid biosynthesis defects other than 21alpha-hydroxylase deficiency, such as defective 11beta-hydroxylation or 3beta-hydroxysteroid dehydrogenase malfunction. The diagnosis of polycystic ovary syndrome was applicable to 12.4%. In addition, our results show that 72% of 281 patients with secondary hirsutism had normal T concentrations, and 55% had a normal FAI. Only 5% of hirsute patients with a normal FAI had elevated DHEAS values. However, 40% showed elevated DHEA levels, while 26% of the women with normal FAI showed androstendione values over the maximal levels in the 79 controls. CONCLUSIONS: Our data suggest that in addition to testosterone and FAI, androstendione and DHEA are significantly helpful parameters in diagnosing hyperandrogenemia in hirsute women. DHEAS was not found to be helpful.     

A prospective assessment of androgen levels in patients with autistic spectrum disorders: biochemical underpinnings and suggested therapies

Impairments in social relatedness and communication, repetitive behaviors, abnormal movement patterns, and sensory dysfunction characterize autism spectrum disorders (ASDs). Seventy consecutive patients with an ASD diagnosis (DSM-IV criteria, >/= 6 years-old) who presented to the Genetic Centers of America for outpatient genetic/developmental evaluations from 2005-2007 were examined. Patients were evaluated using CLIA-approved Laboratory Cooperation of America (LabCorp) testing for: serum testosterone, serum free testosterone, % free testosterone, serum/plasma dehydroepiandrosterone (DHEA), androstendione, and follicle-stimulating hormone (FSH). Morning blood samples collected following an overnight fast, compared to the pertinent reference means, showed significantly increased relative mean levels for: serum testosterone (158%), serum free testosterone (214%), percent free testosterone (121%), DHEA (192%), and androstenedione (173%). By contrast, compared to the pertinent reference mean, the relative mean level of FSH (51%) was significantly decreased. Additionally, at least one of the androgen attributes examined exceeded its recognized laboratory age- and sex-specific reference range in 81.4% (57 of 70) of the patients examined. With respect to their age- and sex-specific reference ranges, females had significantly higher overall mean relative testosterone and relative free testosterone levels than males. Increased androgens in patients diagnosed with ASDs may involve cyclical interactions between the androgen and the transsulfuration pathways, particularly following mercury exposure. A review of therapies that have significantly improved clinical outcomes in ASD patients indicates they share commonality in helping lower androgens. Thus, androgens should be routinely clinically measured in patients with an ASD diagnosis and appropriate androgen-lowering therapies considered for those who have significantly elevated levels.     

The impact of assay sensitivity in the assessment of diseases and disorders in children

Accurate measurement of the low levels of testosterone (T) and estradiol (E(2)) present in normal children and in children with disorders of puberty and sexual development is critical both for appropriate diagnosis and treatment and for clinical research studies. However, measurement of these levels lacks needed precision because of inadequate sensitivity of most commercially available assays and poor accuracy at the low levels found in normal childhood and most disorders. While immunoassays presently do not appear to have the potential to provide more accurate measurements, isotope dilution-gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry techniques offer promise to meet this need to improve clinical care and research.     

Associations of Sex Hormone Concentrations with Health and Life Satisfaction in Elderly Men

ObjectiveTo analyze associations between sex hormone concentrations and self-rated health and life satisfaction, neuropsychiatrie symptoms, or diagnosed depression or dementia in elderly men.MethodsThe study subjects were men from the community-based Lieto Study (N = 517). Subjects were excluded from the study if they were taking exogenous sex hormones or medication for prostate cancer or for benign prostatic hyperplasia or if data for calculating body mass index (BMI) were missing. Thus, 466 men (64 to 97 years old; mean age, 72 years; mean BMI, 26.9 kg/m²) remained for further analysis.ResultsAfter adjustment for age, higher levels of testosterone and free testosterone were associated with better self-rated health. After adjustment for age and BMI, no statistically significant associations were found between sex hormone levels and self-rated health or life satisfaction or most neuropsychiatric symptoms in elderly men. Diagnosed depression was associated with a lower serum testosterone concentration. Higher levels of luteinizing hormone and follicle-stimulating hormone were associated with diagnosed dementia.ConclusionIn this population-based study with high attendance rate, low serum testosterone concentration was associated with diagnosed depression. Subclinical hypogonadism may be associated with diagnosed dementia. Single questions on neuropsychiatric symptoms commonly associated with androgen deficiency seemed to have weak or no correlation with testosterone or free testosterone levels among this group of elderly men. (Endocr Pract. 2007;13:743-749)     

Prostate cancer risk in testosterone-treated men

Men with classical androgen deficiency have reduced prostate volume and blood prostate-specific antigen (PSA) levels compared with their age peers. As it is plausible that androgen deficiency partially protects against prostate disease, and that restoring androgen exposure increases risk to that of eugonadal men of the same age, men using ART should have age-appropriate surveillance for prostate disease. This should comprise rectal examination and blood PSA measurement at regular intervals (determined by age and family history) according to the recommendations, permanently revisited, published by ISSAM, EAU, Endocrine Society….

Testosterone replacement therapy is now being prescribed more often for aging men, the same population in which prostate cancer incidence increases; it has been suggested that administration in men with unrecognised prostate cancer might promote the development of clinically significant disease. In hypogonadal men who were candidates for testosterone therapy, a 14% incidence of occult cancer was found. A percentage (15.2%) of prostate cancer has been found in the placebo group (with normal DRE and PSA) in the prostate cancer prevention study investigating the chemoprevention potential of finasteride.

The hypothesis that high levels of circulating androgens is a risk factor for prostate cancer is supported by the dramatic regression, after castration, of tumour symptoms in men with advanced prostate cancer. However these effects, seen at a very late stage of cancer development, may not be relevant to reflect the effects of variations within a physiological range at an earlier stage.

Data from all published prospective studies on circulating level of total and free testosterone do not support the hypothesis that high levels of circulating androgens are associated with an increased risk of prostate cancer. A study on a large prospective cohort of 10,049 men, contributes to the gathering evidence that the long standing “androgen hypothesis” of increasing risk with increasing androgen levels can be rejected, suggesting instead that high levels within the reference range of androgens, estrogens and adrenal androgens decrease aggressive prostate cancer risk. Indeed, high-grade prostate cancer has been associated with low plasma level of testosterone. Furthermore, pre-treatment total testosterone was an independent predictor of extraprostatic disease in patients with localized prostate cancer; as testosterone decreases, patients have an increased likelihood of non-organ confined disease and low serum testosterone levels are associated with positive surgical margins in radical retropubic prostatectomy.

A clinical implication of these results concerns androgen supplementation which has become easier to administer with the advent of transdermal preparations (patch or gel) that achieve physiological testosterone serum levels without supra physiological escape levels. During the clinical development of a new testosterone patch in more than 200 primary or secondary hypogonadal patients, no prostate cancer was diagnosed.     

Testosterone and sport: current perspectives

Testosterone and other anabolic-androgenic steroids enhance athletic performance in men and women. As a result, exogenous androgen is banned from most competitive sports. However, due to variability in endogenous secretion, and similarities with exogenous testosterone, it has been challenging to establish allowable limits for testosterone in competition. Endogenous androgen production is dynamically regulated by both exercise and winning in competition. Furthermore, testosterone may promote athletic performance, not only through its long-term anabolic actions, but also through rapid effects on behavior. In women, excess production of endogenous testosterone due to inborn disorders of sexual development (DSD) may convey a competitive advantage. For many years, female competitors have been subject to tests of sexual genotype and phenotype known as gender verification. Although gender verification has not identified any normal man competing as a woman, this process has identified women athletes with DSD. As understanding of DSD has expanded in recent years, women with DSD are increasingly able to continue athletic competition.     

Reexamination of testosterone, dihydrotestosterone, estradiol and estrone levels across the menstrual cycle and in postmenopausal women measured by liquid chromatography-tandem mass spectrometry

Measuring serum androgen levels in women has been challenging due to limitations in method accuracy, precision sensitivity and specificity at low hormone levels. The clinical significance of changes in sex steroids across the menstrual cycle and lifespan has remained controversial, in part due to these limitations. We used validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays to determine testosterone (T) and dihydrotestosterone (DHT) along with estradiol (E2) and estrone (E1) levels across the menstrual cycle of 31 healthy premenopausal females and in 19 postmenopausal females. Samples were obtained in ovulatory women in the early follicular phase (EFP), midcycle and mid luteal phase (MLP). Overall, the levels of T, DHT, E2 and E1 in premenopausal women measured by LC-MS/MS were lower overall than previously reported with immunoassays. In premenopausal women, serum T, free T, E2, E1 and SHBG levels peaked at midcycle and remained higher in the MLP, whereas DHT did not change. In postmenopausal women, T, free T, SHBG and DHT were significantly lower than in premenopausal women, concomitant with declines in E2 and E1. These data support the hypothesis that the changes in T and DHT that occur across the cycle may reflect changes in SHBG and estrogen, whereas in menopause, androgen levels decrease. LC-MS/MS may provide more accurate and precise measurement of sex steroid hormones than prior immunoassay methods and can be useful to assess the clinical significance of changes in T, DHT, E2 and E1 levels in females.     

Serum levels of 5-androstene-3 beta,17 beta-diol sulphate, 5 alpha-androstane-3 alpha, 17beta-diol sulphate and glucuronide, in late onset 21-hydroxylase deficiency

Serum sulphates of 5-androstene-3 beta,17 beta-diol (5-ADIOL-S), 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-DIOL-S) and dehydroepiandrosterone (DHEA-S), as well as 5 alpha-androstane-3 alpha,17 beta-diol glucuronide (3 alpha-DIOL-G) and unconjugated androstenedione (AD) and testosterone (T), sex hormone binding globulin (SHBG), free androgen index (FAI) and 17 alpha-hydroxyprogester-one (17OHP) were measured by specific radioimmunoassays (RIA) in 14 women with late-onset 21-hydroxylase deficiency (LOCAH), and in normal women (n = 73). The diagnosis of LOCAH was made on the finding of a (17OHP) response level greater than 30 nmol/l following ACTH stimulation, and/or an elevation of urinary metabolites of 17OHP. Mean values for serum concentrations of all steroids measured and the free androgen index (100 X T nmol/l divided by SHBG nmol/l) were significantly elevated, and SHBG levels depressed in patients with LOCAH. These studies show that in LOCAH, in addition to the unconjugated steroids AD and T, the sulphoconjugated steroids DHEA-S, 5-ADIOL-S and 3 alpha-DIOL-S are increased, as is the glucuronide conjugate 3 alpha-DIOL-G and the index of bioavailable testosterone (FAI), and that mean SHBG levels are depressed. These data suggest that as well as AD, 5-ADIOL-S and DHEA-S may act as pro-hormones for more potent steroids (T and 5 alpha-dihydrotestosterone) in peripheral tissues, while 3 alpha-DIOL-S and 3 alpha-DIOL-G may both reflect peripheral androgen metabolism in patients with LOCAH.     

Testosterone levels and cognitive functioning in women with polycystic ovary syndrome and in healthy young women

We investigated the possible influence of testosterone (T) on cognitive functioning in women with polycystic ovary syndrome (PCOS), an endocrine disorder associated with elevated levels of free testosterone (free T). Performance on a battery of neuropsychological tests in 29 women with elevated free T levels due to PCOS was compared to the performance of 22 age- and education-matched, healthy control women with free T levels in the normal female range. Women with PCOS had significantly higher levels of free T (estimated by the free androgen index) and demonstrated significantly worse performance on tests of verbal fluency, verbal memory, manual dexterity, and visuospatial working memory than the healthy control women. No differences between the groups were found on tests of mental rotation, spatial visualization, spatial perception, or perceptual speed. These results suggest that, in women, elevations in free T may be associated with poorer performance on cognitive tasks that tend to show a female advantage.     

Increasing women's sexual desire: The comparative effectiveness of estrogens and androgens

Both estradiol and testosterone have been implicated as the steroid critical for modulating women's sexual desire. By contrast, in all other female mammals only estradiol has been shown to be critical for female sexual motivation and behavior. Pharmaceutical companies have invested heavily in the development of androgen therapies for female sexual desire disorders, but today there are still no FDA approved androgen therapies for women. Nonetheless, testosterone is currently, and frequently, prescribed off-label for the treatment of low sexual desire in women, and the idea of testosterone as a possible cure-all for female sexual dysfunction remains popular. This paper places the ongoing debate concerning the hormonal modulation of women's sexual desire within a historical context, and reviews controlled trials of estrogen and/or androgen therapies for low sexual desire in postmenopausal women. These studies demonstrate that estrogen-only therapies that produce periovulatory levels of circulating estradiol increase sexual desire in postmenopausal women. Testosterone at supraphysiological, but not at physiological, levels enhances the effectiveness of low-dose estrogen therapies at increasing women's sexual desire; however, the mechanism by which supraphysiological testosterone increases women's sexual desire in combination with an estrogen remains unknown. Because effective therapies require supraphysiological amounts of testosterone, it remains unclear whether endogenous testosterone contributes to the modulation of women's sexual desire. The likelihood that an androgen-only clinical treatment will meaningfully increase women's sexual desire is minimal, and the focus of pharmaceutical companies on the development of androgen therapies for the treatment of female sexual desire disorders is likely misplaced.     

Optimizing Diagnostic Accuracy and Treatment Decisions in Men With Testosterone Deficiency

ObjectiveThis narrative review offers a guideline-based approach for optimizing diagnostic evaluation and treatment decision making in men being evaluated for testosterone deficiency.MethodsA narrative review.ResultsTestosterone deficiency is a clinical syndrome that results from the inability of the testes to produce normal amounts of testosterone and is characterized by a constellation of symptoms and signs associated with consistently low testosterone concentrations. The diagnosis of testosterone deficiency is made by the ascertainment of symptoms and signs; the measurement of total and, if indicated, free testosterone levels in early-morning fasting samples on ≥2 days; the measurement of luteinizing hormone and follicular-stimulating hormone levels to distinguish primary from secondary hypogonadism; and an additional evaluation to ascertain the cause of testosterone deficiency. Nonspecificity of symptoms and signs, variations in testosterone levels over time, inaccuracy in the measurement of total and free testosterone levels, variations in binding protein concentrations, and suboptimal reference ranges contribute to diagnostic inaccuracy. Testosterone treatment is indicated for men with symptomatic testosterone deficiency. Testosterone treatment should be avoided in men with prostate or breast cancer, erythrocytosis, thrombophilia, increased risk of prostate cancer or severe lower urinary tract symptoms without prior urologic evaluation, a recent major adverse cardiovascular event, uncontrolled heart failure, or severe untreated sleep apnea. Testosterone replacement therapy should be accompanied by a standardized monitoring plan.ConclusionA shared decision of the patient and physician to treat should be guided by the consideration of the burden of symptoms, potential benefits and risks, patient’s values, and the cost and burden of long-term treatment and monitoring.     

Le déficit androgénique lié à l’âge: du diagnostic biologique au traitement substitutif

There is increasing interest in the assessment of testicular function in aging men, probably because of an increasing number of males above 60 years and because of the emerging gap in the medical management of aging between men and women. In the last three decades, the endocrinological problems of menopause have been thoroughly taken into consideration, while the decline in testis activity in the so called andropause was only recently recognized to deserve a similar interest. In fact, testis endocrine function is not so easy to evaluate in elderly men: total testosterone (tT) level declines very slowly and it is a fallacious index of testis function because of the increase in testosterone/estradiol binding globulin (TeBG) levels in aging males. Free testosterone level is an accurate index when measured by reference techniques, while routine direct assays using testosterone analogues have been proven to be unreliable diagnostic tools. The measurement of bioavailable testosterone (bT) after ammonium sulfate precipitation of TeBG-bound testosterone is currently considered as the method of choice for diagnosing ADAM syndrome. Indeed, in aging males, bT levels are more closely correlated than tT with bone mineral density, muscle strength and muscle mass. Bioavailable estradiol is also a reliable index of testis aging in elderly males and is strongly correlated with bone mineral density. Unfortunately a serious expertise is needed for accurate measurement of bioavailable estradiol levels. Another difficulty in the diagnosis of ADAM syndrome in the uncertainty in the bT threshold to be taken into account. The 5th percentile of bT levels in young adult men can be arbitrarily choosen; however, there is no definite proof that such a threshold is totally appropriate, since no data are available regarding the evolution with years of androgen receptor sensitivity. Nevertheless, identifying androgen deficiency by means of bT measurement may lead to hormone replacement therapy, at least as a therapeutic test. Several formulations of testosterone are currently available using oral, intra-muscular and transdermal routes. Testosterone undecanoate (Pantestone®) is given orally and is supposed to reach the blood stream via the lymph thoracic channel. Intra-muscular testosterone in oil (Androtardyl® and Testosterone Heptylate®) can maintain high testosterone levels for two to three weeks, but can also induce supra-physiological levels of testosterone and dihydrotestosterone (DHT) within the first week after injection. Transdermal formulations have been recently proposed as non-invasive ways to administer testosterone while by-passing liver metabolism. Permeation enhanced transdermal system (Androderm®) can mimic the testosterone circadian rythm, but testosterone levels may be supra-physiological for several hours. DHT levels however are generally maintained whithin physiological values. Testosterone gel (Androgel®) can induce stable and physiological levels of testosterone, DHT and estradiol. Care should be taken to avoid contamination of the familial environment by testosterone after its application. The choice between these formulations depends obviously on the patient’s needs, the patient’s requests, and the patient’s compliance with a particular formulation.     

Androgens in women

The role of androgen treatment in women remains controversial. The proposed “Female Androgen Insufficiency Syndrome” (Fertility and Sterility, April 2002) describes a number of non-specific symptoms including unexplained fatigue, decreased well being/dysphoric mood and/or blunted motivation and diminished sexual function. An estimated 40% of women experience sexual dysfunction, highlighting the need for ongoing research into this field in order to fully define the possible contribution of androgen insufficiency. The increasing availability of products, such as dehydroepiandrosterone (DHEA) supplements also points to the need for controlled studies to assess the safety of these and other preparations.

Measurement of androgens in women requires sensitive assays with the ability to detect low levels and a narrow range with precision. Normal ranges of androgens for women of reproductive and post-reproductive age remain poorly defined. Debate exists as per importance of measurement of free versus total testosterone, with the ‘free androgen index’ offering an alternative method of assessment of testosterone availability.

Testosterone treatment is being developed for women in the form of transdermal patches, gels or cream, with percutaneous implants in common usage in some countries. Recent research has highlighted alternative means of administration, such as oral inhalation or buccal lozenge. DHEA is widely available in some countries. Research to date has demonstrated improvements in libido and sexual function, mood and well being. Evidence points to other potential benefits of androgen treatment, including preservation of bone mass, a possible protective role in breast cancer and beneficial effects on cognition.

Adverse effects of androgen treatment in women are dose-dependent and include virilisation, mood disturbance and acne. These are uncommon if appropriate doses are administered and highlight the need for treatment to be closely monitored clinically and biochemically. Beneficial effects of testosterone treatment in post-menopausal women with lowered androgen levels have been well documented, and preliminary evidence suggests a role for treatment in pre-menopausal women with symptoms and lowered testosterone levels.     

Circadian variations of serum sex hormone binding globulin binding capacity in normal adult men and women

Diurnal variations of serum sex hormone binding globulin (SHBG), testosterone (T) and estradiol (E2) in five normal adult men and five normal adult women were investigated. SHBG binding capacity was measured by both polyacrylamide gel electrophoresis and dextran-coated charcoal technique (DCC); T and E2 were assayed by RIA and free T and free E2 were determined by means of equilibrium dialysis. In male subjects the variations of SHBG binding capacity was associated with the changes of total T, free T and T/SHBG index, which had the highest concentrations in the morning and the lowest levels in the evening during the 24 h test period, but percentage free T remained unchanged. Serum protein concentrations did not change significantly during 24 h. No significant diurnal changes of SHBG binding capacity, total E2, free E2, percentage free E2 and percentage free T were found in female subjects in the mid-luteal phase of the menstrual cycle, although significant fluctuations of total T, free T and T/SHBG index were observed throughout the day. The results suggested that SHBG may play a buffer role in the presence of fluctuations of testosterone production during 24 h period, allowing stabilization of a bioactive fraction of the hormone both in normal adult male and female. However, the concentrations of T in normal adult women may be too low to drive any change of SHBG levels while there were no significant variations of E2 throughout a day in the mid-luteal phase of the menstrual cycle.     

Déficit Androgénique Lié à l’Age

In contrast with the abrupt cessation of ovarian function at menopause in women, alteration of testicular functions in aging males is partial and progressive. Several cross-sectional studies have demonstrated an age-related decrease of testosterone levels in men. This decrease has also been observed when only men in good health are included in such studies. This age-related decline of testosterone levels has been recently confirmed by a longitudinal study including a large number of subjects. The progressive decline begins early, from the late thirties, and continues at a constant rate throughout the subject’s lifetime. Since SHBG increases with age, free testosterone and non-SHBG-bound testosterone (referred to as bioavailable testosterone) decrease more markedly than total testosterone. As variations of SHBG levels (mainly a decrease in obese and/or insulin-resistant subjects) are often encountered in clinical practice and as it is difficult to reliably measure free testosterone, bioavailable testosterone appears to be the better index to diagnose androgen deficiency in the aging male. Elevation of basal LH levels, decrease of hCG-induced testosterone levels and reduction of Leydig cell number demonstrate the testicular origin of hypogonadism. However, gonadotropic function is also relatively altered with aging. As a result of this alteration of gonadotropic function, LH level is not a reliable index of hypogonadism in the aging male. None of the androgen-dependent functions that are altered with aging, i.e. libido, erectile function, sense of well-being, muscle mass, muscle strength, fat mass, bone mass, etc., are exclusively controlled by androgens. In clinical practice, the indication for androgen replacement therapy must therefore be based on a combination of clinical symptoms and a reduction of bioavailable testosterone below a certain cut-off value, indicating “significant” hypogonadism.     

Androgen secretion in ectopic ACTH syndrome and in Cushing's disease: modifications before and after surgery.

The role of ACTH in the control of adrenal androgen secretion is known, although the possible existence of other regulatory factors has been also suggested. While some data concerning Cushing's disease have been reported, only few studies concerned androgen levels in ectopic ACTH secretion. The aim of this study was to evaluate serum DHEA-S, androstenedione (A) and testosterone (T) levels in 36 women with ACTH-dependent Cushing's syndrome (30 with Cushing's disease and 6 with ectopic ACTH secretion) before and after surgery. Two men with ectopic ACTH production were also studied. In 30 women with Cushing's disease serum DHEA-S (9.6 +/- 0.9 micromol/l), A (15.2 +/- 1.2 nmol/l) and T (4.1 +/- 0.5 nmol/l) were higher than in controls (p < 0.01): elevated DHEA-S, A and T values were found in 8, 18 and 17 cases, respectively. After adenomectomy in 15 apparently cured patients DHEA-S, A and T levels were low at 1 - 3 months and at 6 - 12 months after surgery. At 18 - 24 months, DHEA-S remained low in spite of cortisol normalisation. In ectopic Cushing's syndrome, A levels were significantly higher (23.1 +/- 4.9 nmol/l) than in Cushing's disease (p < 0.05), while no differences were found in DHEA-S and T levels. Two patients had elevated DHEA-S values, 3 women had high T levels and 7 of the 8 patients had very high A concentration that was lowered in 3 operated cases. In conclusion, the pattern of adrenal androgen secretion is rather different in patients with pituitary or with ectopic Cushing's syndrome. While the frequency of DHEA-S and T alterations is similar, androstenedione secretion is greatly increased in the latter condition. It is suggested that in ACTH-secreting non-pituitary tumours, the production of a POMC-derived peptide, although unidentified, may lead to preferentially stimulated androstenedione secretion, without affecting other enzymatic pathways.