Testosterone levels during systemic and inhaled corticosteroid therapy.

Testosterone has importance both as a sex hormone and as an anabolic steroid promoting bone formation. Osteoporosis is associated with both hypogonadism and corticosteroid therapy. Testosterone levels are reduced by long term prednisolone treatment. Although high dose inhaled corticosteroid therapy may cause a variety of systemic effects including adrenal suppression, dermal thinning and a reduction in total bone calcium, its effect on testosterone levels is not known. Testosterone, luteinizing hormone, follicle stimulating hormone and sex hormone binding globulin were therefore measured in 35 male patients with respiratory disease attending an outpatient clinic (median age 58, range 21-75 years). They were grouped according to steroid therapy and compared with 19 age matched controls. Mean (SD) testosterone levels were 33% lower in 12 men on long term oral prednisolone [14.5 (6.0) nmol 1-1] than in controls [21.7 (6.3) nmol 1-1], but were not significantly reduced in 10 patients on low dose inhaled beclomethasone [200-800 micrograms day-1: 19.7 (3.7)] nor in 13 men taking high dose inhaled beclomethasone [1500-2,250 micrograms day-1: 17.9 (5.6)]. Levels of luteinizing hormone, follicle stimulating hormone and sex hormone binding globulin were similar in all four groups. These cross sectional data confirm that long term systemic corticosteroid therapy reduces testosterone levels. However, testosterone was reduced by only 18% (NS) by long term inhaled corticosteroids. Other mechanisms to explain the disordered bone metabolism should now be explored.

Acute cholinergic blockade with low dose pirenzepine reduces the insulin and glucose responses to a mixed meal in obese women with the polycystic ovary syndrome.

OBJECTIVES: Pirenzepine, a selective muscarinic cholinergic antagonist, reduces plasma insulin and plasma glucose responses to a mixed meal in a dose dependent fashion in normals and in patients with non-insulin dependent diabetes. We have studied the effects of pirenzepine on plasma insulin, plasma glucose, growth hormone (GH), androstenedione, testosterone, insulin-like growth factor-I (IGF-I) and IGF binding protein 1 (IGFBP-1) responses to a mixed meal in obese clinically hyperandrogenic women with the polycystic ovary syndrome. SUBJECTS AND METHODS: Six obese women with polycystic ovary syndrome (BMI range 27.3-39.8 kg/m2) were studied in random sequence, and received either placebo or pirenzepine (single doses of 50, 100, or 200 mg) one hour before a standard test meal. Blood was sampled every 15 minutes for 2 hours after the meal and every 30 minutes thereafter for a total of 4 hours. RESULTS: Mean fasting plasma insulin concentrations were increased. Peak post-prandial plasma insulin concentrations were reduced significantly by all three doses used. Post-prandial integrated plasma insulin concentrations were reduced by the two higher doses. Peak post-prandial plasma glucose concentrations were also reduced. The late post-prandial GH surge was significantly suppressed by all three doses. However, plasma androstenedione, testosterone, IGF-I and IGFBP-1 concentrations were not significantly different when placebo was compared with pirenzepine 200 mg. CONCLUSIONS: Acute cholinergic muscarinic blockade with pirenzepine significantly reduces meal stimulated plasma insulin and plasma glucose concentrations in clinically hyperandrogenic women with polycystic ovary syndrome. The ability of pirenzepine to reduce plasma insulin without worsening glycaemia is a particular advantage and may be therapeutically relevant. Further studies are under way to assess the usefulness of pirenzepine in long-term suppression of plasma insulin in this group of patients.

Maternity blues and major endocrine changes: Cardiff puerperal mood and hormone study II.

OBJECTIVES: To define relation between mood and concentrations of progesterone and cortisol during perinatal period to test hypothesis that rapid physiological withdrawal of steroid hormones after delivery is associated with depression. DESIGN: Prospective study of primiparous women from two weeks before expected date of delivery to 35 days postpartum. SETTING: Antenatal clinic in university hospital, obstetric inpatient unit, patients' homes. SUBJECTS: 120 of 156 primiparous women interviewed. Remainder excluded because of major marital, socioeconomic, or medical problems or because caesarean section required. MAIN OUTCOME MEASURES: Concentrations of progesterone and cortisol in saliva samples; women's moods assessed by various scores for depression. RESULTS: Changes in salivary progesterone and cortisol concentrations were similar to those already characterised for plasma. Peak mean score for maternity blues (5.3 on Stein scale) was on day five postpartum (P < 0.02 compared with mean scores on other postpartum days). High postpartum scores for maternity blues were associated with high antenatal progesterone concentrations on day before delivery (P < 0.05), with high rate of rise of antenatal progesterone concentrations (P < 0.05), with decreasing progesterone concentrations from day of delivery to day of peak blues score (P > or = 0.01), and with low progesterone concentrations on day of peak blues score (P < 0.01). Seventy eight women were designated as having maternity blues (peak score > or = 8 on Stein scale) while 39 had no blues. Women with blues had significantly higher antenatal progesterone concentrations and lower postnatal concentrations than women without blues (geometric mean progesterone concentrations: one day before delivery 3860 pmol/l v 3210 pmol/l respectively, P = 0.03; ten days postpartum 88 pmol/l v 114 pmol/l, P = 0.048). Cortisol concentrations were not significantly associated with mood. CONCLUSION: Maternal mood in the days immediately after delivery is related to withdrawal of naturally occurring progesterone.

Endogenous sex hormones and ischemic heart disease in men. The Caerphilly prospective study.

Numerous case-control studies have suggested that elevated levels of endogenous estrogen and low levels of testosterone are associated with ischemic heart disease (IHD) in men. These findings were tested in the Caerphilly study of 2,512 men from the general population who were aged 45-59 years at baseline and were followed for 5 years. Some 153 men experienced a new episode of IHD (fatal and nonfatal) during the period of follow-up. Baseline values of estradiol were marginally higher in subjects who developed IHD than in those who did not, but the difference was not statistically significant. Plasma values of testosterone were similar in the two groups. Among quintiles of the distribution of the hormone values, the incidence of IHD was similar in the case of estradiol; there was also no clear trend in the case of testosterone. These findings provide no support for the suggestion that plasma estradiol or testosterone are primary risk factors for IHD, although the associations between plasma testosterone and other probable risk markers (triglycerides, insulin, body mass index, and high density lipoprotein cholesterol) indicate the possibility that testosterone may play an indirect role in the pathogenesis of IHD.

Cardiff puerperal mood and hormone study. 1. Saliva steroid hormone profiles in late pregnancy and the puerperium: endocrine factors and parturition.

Participants were 120 primiparous women who had vaginal delivery of a non-handicapped child. Saliva was collected twice daily through parturition to day 35 post-partum. In the prepartum, a highly significant circadian rhythm was seen in cortisol, with a lower-amplitude rhythm in progesterone (AM/PM = 1.12). Evening samples showed a rise in cortisol, with a highly significant rise on day -1. The rise was small. The fall in progesterone in the 3 days before parturition was also small (approximately 6%). Neither change provides an obvious trigger for parturition.

Salivary testosterone levels and major depressive illness in men.

Studies of testosterone levels in patients with major depressive illness have produced varying results, plasma levels usually being reported. Saliva levels reflect 'free' plasma testosterone, and a pilot study of 11 men with major depression with melancholia, who underwent a standard dexamethasone suppression test, is described. There were no significant differences in testosterone levels compared with an age-matched control group. In the patient group, pre-dexamethasone levels correlated significantly and negatively with depression ratings on the 21-item Hamilton and the Montgomery and Asberg depression scales, and also with state anxiety measured on the Spielberger scale.

Seasonal variation and the results of the dexamethasone suppression test.

There is controversy over the presence of a circannual rhythm in cortisol values in samples provided by depressed patients after a standard dexamethasone suppression test (DST). Post-DST cortisol values from patients admitted to an acute psychiatric ward over a 2-year period have therefore been analysed by appropriate statistical tests. No evidence was found for significant seasonal variation.

A robust assay for dexamethasone in plasma using a heterologous 125I radioligand and a magnetizable solid-phase antiserum.

An assay using an antiserum raised against a dexamethasone 21-hemisuccinate conjugate and the heterologous radioligand dexamethasone 21-(carboxymethyl) ether was developed, validated, and used to study the pharmacokinetics of this steroid for 12 h following administration to patients with congenital adrenal hyperplasia. Coupling the antiserum to magnetizable cellulose allowed rapid separation of bound/free steroid. A C-21 rather than a C-3 antiserum was used to minimize interference with a main metabolite, 6 beta-hydroxydexamethasone. Close correspondence of assay (0.35 nmol/L) and curve (0.25 nmol/L) sensitivities suggests that interference by matrix effects is minimal. This was confirmed by good agreement in data from the in-house assay and that of a reference procedure. Good precision was demonstrated by the precision profile and Shewhart chart quality control data. The latter also demonstrated the assay was robust and reliable in routine practice.

Comparisons of plasma and salivary cortisol determinations for the diagnostic efficacy of the dexamethasone suppression test.

The current status of the saliva dexamethasone suppression test (DST) is discussed and results from the literature reviewed. Evidence is presented that demonstrates that the efficacy of the salivary-based test is equal to that of the plasma DST provided that specifically developed radioimmunoassays are used for determination of salivary cortisol. Such evidence relied on measurement of cortisol in 300 matched samples of plasma and saliva provided by patients admitted to a routine psychiatric ward over a 2-year period. The results according to diagnosis (DSM-III categories) were in line with those generally reported. The influence of anticholinergic medication was examined: this had no significant effects on the performance of the plasma or salivary-based DST.

Chronobiology in laboratory medicine: principles and clinical applications illustrated from measurements of neutral steroids in saliva.

A number of chronobiological principles, as they pertain to the practice of laboratory medicine, have been discussed. Without doubt, salivary steroid assays are valuable tools for use in clinical studies, not necessarily as a single time-qualified sample but more often as a series of samples that will describe the underlying endocrinological time-structure. It is also important to appreciate that melatonin, certain drugs, and many dietary constituents such as phyto-oestrogens, are among the myriad of substances that can be monitored, and so hold great promise for the chronobiologist interested in the use of saliva as a sampling medium, both in the present and in the future.

Salivary steroids and psychometric parameters in male marathon runners.

Testosterone and cortisol in male marathon runners (n = 11) were determined in saliva samples (n = 28) collected during the three rest days preceding a competitive marathon and in the samples collected at 08.00h on the race day. An Eysenck Personality Inventory was completed on the first rest day and psychological state was assessed on rest days and on the morning of the marathon by completion of visual analogue scales for anxiety, depression, hostility and libido at four times each day. Anxiety, depression and hostility were positively inter-correlated. Extraversion and depression were negatively correlated. At 08.00h on the day of the marathon, anxiety and hostility scores were significantly higher than those on rest days, but depression and libido scores were unchanged. No relationship was found between depression or libido and any hormonal parameter. Race day cortisol correlated negatively with hostility, and changes in cortisol (09.00h) between the race day and the mean rest-day levels correlated with the corresponding changes in anxiety.

Salivary testosterone levels and the progress of puberty in the normal boy.

Salivary testosterone (ST) levels were measured in 84 boys aged 7.3-16.2 from the Edinburgh Growth Study. The correlation coefficient between matched plasma/saliva samples was 0.88. Six samples were collected over the course of one day from 0900 to 2100 h each month in the majority of the children for 4 consecutive months. Mean daily ST levels showed a significant rise between each pubertal stage (genital (G) and pubic hair (PH]. The rise in ST became more rapid once a mean testicular volume (MTV) of 10 ml had been reached. The diurnal rhythm was assessed by individual curve fitting on the log scale and by cosinor analysis. A rhythm was present prepubertally and developed into a pattern similar to that of the adult rhythm by stage G3. The monthly rate of rise of ST was greatest at stage G4. A significant rise in ST levels was detectable immediately prior to an increase in MTV to 3 ml. This allowed earlier recognition of the clinical onset of puberty at testicular volume of 3 ml, which in this group occurred at 10.9 (SD 0.9) years. ST is a non-invasive and sensitive method for the serial monitoring of gonadal function in the prepubertal and adolescent boy.

The hormonal environment of post-natal depression.

The incidence of post-natal depression is high, and dramatic changes in steroid hormones and prolactin occur in the post-partum period. In an attempt to correlate these events, 147 mothers, six to eight weeks after delivery of a healthy infant, completed standard psychological tests, including the Edinburgh, Montgomery-Asberg, and Raskin scales. They also provided matched samples of plasma for assay of cortisol, oestradiol, progesterone and prolactin, and saliva for assay of cortisol and progesterone. All steroid concentrations were within the appropriate normal ranges. Of the mothers, 14.9% were depressed on all three scales. Significant correlations were seen between depression ratings and salivary progesterone and prolactin. In bottle-feeders, salivary progesterone was positively associated with depression, whereas in breast-feeders it was negatively associated. Plasma prolactin levels were inappropriately low in depressed breast-feeders. These data indicate that differing therapies may be appropriate for depression in breast- and bottle-feeders.

170H-progesterone rhythms in congenital adrenal hyperplasia.

Serial blood spot and saliva samples were collected at home by 18 patients being treated for congenital adrenal hyperplasia to determine the circadian rhythm of 170H-progesterone as an index of therapeutic control. There was a strong correlation between the magnitude of the circadian fall and a single morning measurement of the plasma testosterone concentration taken near the time of the 170H-progesterone rhythm samples. Poor control in pubertal girls produced an exaggerated circadian fall in 170H-progesterone concentrations that were raised at all sampling times. Optimal control (plasma testosterone 1.5-2.5 nmol/l) was associated with blood spot and salivary 170H-progesterone concentrations at 0800 hours of between 30-70 nmol/l and 260-1000 pmol/l, respectively, falling thereafter to less than 10 nmol/l and less than 150 pmol/l, respectively. Similar results were obtained in prepubertal patients. Nomograms have been constructed to interpret the daily profiles of blood spot or salivary measurements of 170H-progesterone, or both. The analysis of 170H-progesterone circadian rhythms is useful in monitoring treatment in patients with congenital adrenal hyperplasia, particularly those who may be overtreated.

Androstenedione rhythms in saliva in congenital adrenal hyperplasia.

Serial samples of saliva were collected at home by 17 patients being treated for congenital adrenal hyperplasia to determine the circadian rhythm of androstenedione as an index of therapeutic control. Single samples of blood for measurement of plasma testosterone, 170H-progesterone, and androstenedione concentrations were collected from these and a further seven patients for comparison. Plasma androstenedione concentrations showed a close correlation with plasma concentrations of 170H-progesterone and testosterone. There was a strong correlation between the salivary androstenedione profiles and plasma testosterone concentrations in pubertal girls. Concentrations of androstenedione in saliva decreased during the day but remained raised at each sampling time in relation to plasma testosterone concentrations. Salivary androstenedione profiles are shown as nomograms to distinguish the degree of therapeutic control. The concentration of androstenedione, measured in plasma or saliva, is an alternative marker to monitor control of treatment in congenital adrenal hyperplasia. The measurement in saliva is a useful index of androgen production when blood sampling is difficult.