Sex steroid hormones and cognitive functioning in healthy, older men

The precise impact of age-related changes in hormone levels on cognition in men is still unclear due to differing study designs and contradictory findings. This study was undertaken to examine the relationship between endogenous sex hormone levels and cognitive functioning in healthy older men using a comprehensive battery of neuropsychological tests and measurement of serum sex hormone levels. Verbal learning and memory, visual-motor processing, spatial abilities, working memory and attention, and levels of testosterone and estradiol were evaluated in 54 healthy older men. Regression analyses revealed significant curvilinear associations between working memory function and both free and bioavailable testosterone levels, suggesting that an optimal hormone level may exist for maximal performance on tasks of executive/frontal lobe functioning. However, no other relationships were evident between either estradiol or testosterone levels and any of the other cognitive functions evaluated. Hormone assays performed at the end of the study revealed that a considerable portion of the healthy elderly men in our sample met criteria for hypogonadism and suggests that their low hormone levels may have mitigated against discovering other significant hormone-cognition relationships.     

Effects of menstrual cycle phase and oral contraceptive use on verbal memory

Surgical or pharmacological suppression of ovarian hormones leads to declines in verbal memory, and estrogen treatment reverses these deficits. In the current study, we investigated the effects of menstrual cycle phase and oral contraceptives on verbal memory, as measured by the California Verbal Learning Test, in two groups of premenopausal women — 16 naturally cycling women and 20 current users of estrogen-based oral contraceptives (OCs). Naturally cycling women were assessed twice — once during the early follicular phase (Days 2-4) and once during the midluteal phase (Days 20-22) of the menstrual cycle. OC users were tested on the same cycle days, corresponding to inactive and active pill phases, respectively. We predicted that naturally cycling women would show improved verbal memory during the midluteal phase, when estradiol levels are high, compared with the follicular phase, when estradiol levels are low. We also predicted that OC users, who show no change in endogenous estradiol across the cycle, would show no change in verbal memory. Contrary to predictions, naturally cycling women showed no changes in verbal memory across the cycle, whereas OC users showed enhanced memory during the active pill phase (p < .05). None of the secondary cognitive outcome measures varied with cycle phase or OC use including measures of visuospatial memory, verbal fluency, visuospatial abilities, and attention. Overall, these results suggest that verbal memory performance in premenopausal women varies across the cycle with OC use, but does not vary systematically with changes in endogenous estradiol.     

The effect of rapid and depot testosterone and estradiol on spatial performance in water maze

Men and women differ in some cognitive functions including spatial abilities. These differences seem to be affected by sex steroids, but the results are controversial. The aim of this work is to describe the effects of rapid or depot testosterone and estradiol on spatial memory in rats. Thirty-two adult male Wistar rats were divided into 6 groups. Five groups were gonadectomized, and one group was left as control. Castrated groups received sterile oil, testosterone isobutyras, testosterone propionate, estradiol dipropionate or estradiol benzoate. We evaluated spatial performance (escape latency, overall improvement, and time in the quadrant after platform removal) of the rats in a spatial water maze. Animals receiving exogenous sex steroids showed higher plasma concentrations of the particular hormones. Experimental groups improved during the acquisition spatial trials in the water maze. No significant differences between the groups during probe trial were found. In overall improvement, the testosterone depot and estradiol depot groups showed less improvement in comparison to the control groups (P<0.05). No differences in respect to administered hormones were found in corresponding receptor gene expression in hippocampus. In conclusion, exogenous testosterone affects spatial memory of adult castrated males.     

Evidence that androgenic and estrogenic metabolites contribute to the effects of dehydroepiandrosterone on cognition in postmenopausal women

Prior studies of the effects of dehydroepiandrosterone (DHEA) on cognition have produced complex and inconsistent results. We hypothesize that these results may arise, in part, because of DHEA's metabolism into estrogens and androgens that produce opposing effects on cognition. Our study administered 50 mg of oral DHEA daily for 4 weeks in a placebo-controlled crossover design to six postmenopausal women. We measured blood levels of androgens (total testosterone, free testosterone, DHEA, DHEAS), estrogens (estradiol, estrone), and cognitive performance on recognition memory, perceptual identification, digit span memory, and visual attentional vigilance under both drug and placebo conditions. Multiple regression models incorporating the factors of age and body mass index (BMI) were used to ascertain the relation between sex steroids and cognitive performance. Our results demonstrated that estrogens produced a positive effect on recognition memory, while androgens produced a negative effect. This pattern reversed in perceptual identification with estrogens producing a negative effect and androgens producing a positive effect. In addition, BMI produced a negative effect on digit span memory, age produced a negative effect on perceptual identification, and androgens produced a negative effect on visual attentional vigilance. These results help, in part, to explain DHEA's complex effects on cognition. The diverse effects of sex steroids across tasks underscore the importance of identifying the specific cognitive mechanisms influenced by sex steroids and emphasizes that one should not expect sex steroids to produce homogeneous effects across cognitive tasks.     

Increased memory load-related frontal activation after estradiol treatment in postmenopausal women

Prior research shows that menopause is associated with changes in cognition in some older women. However, how estrogen loss and subsequent estrogen treatment affects cognition and particularly the underlying brain processes responsible for any cognitive changes is less well understood. We examined the ability of estradiol to modulate the manipulation of information in working memory and related brain activation in postmenopausal women. Twenty healthy postmenopausal women (mean age (SD) = 59.13 (5.5)) were randomly assigned to three months of 1 mg oral 17-β estradiol or placebo. At baseline and three months later each woman completed a visual verbal N-back sequential letter test of working memory during functional magnetic resonance imaging (fMRI). The fMRI data showed that women who were treated with estradiol for three months had increased frontal activation during the more difficult working memory load conditions compared to women treated with placebo. Performance on the verbal working memory task showed no difference between estradiol and placebo treated subjects. These data are consistent with prior work showing increases in frontal activation on memory tasks after estrogen treatment. However, this is the first study to show that estrogen-induced increases in brain activity were tied to cognitive load during a verbal working memory task. These data suggest that estradiol treatment effects on cognition may be in part produced through modulation of frontal lobe functioning under difficult task conditions.     

Effects of GH and/or sex steroids on circulating IGF-I and IGFBPs in healthy, aged women and men

Circulating GH, IGF-I, IGFBP-3, and sex steroid concentrations decrease with age. GH or sex steroid treatment increases IGFBP-3, but little is known regarding the effects of these hormones on other IGFBPs. We assessed the effects of 26 wk of administration of GH, sex steroids, or GH + sex steroids on AM levels of IGF-I, IGFBPs 1-5, insulin, glucose, and osteocalcin and 2-h urinary excretion of deoxypyridinolline (DPD) cross-links in 53 women and 71 men aged 65-88 yr. Before treatment, in women and men, IGF-I was directly related to IGFBP-3 (P < 0.001 and P < 0.0001) and IGFBP-1 to IGFBP-2 (P = 0.0001). In women, IGFBP-1 was inversely related to insulin (P < 0.0005) and glucose (P < 0.005) and IGFBP-4 to osteocalcin (P < 0.01). IGFBP-4 and IGFBP-5 were not significantly related to DPD cross-links. GH and/or sex steroid increased IGF-I levels in both sexes, with higher concentrations in men (P < 0.001). In women, the IGF-I increment after GH was attenuated by hormone replacement therapy (HRT) coadministration (P < 0.05). Hormone administration also increased IGFBP-3. IGFBP-1 was unaffected by GH + sex steroids, whereas GH decreased IGFBP-2 by 15% in men (P < 0.05). Hormone administration did not change IGFBP-4, whereas in men IGFBP-5 increased by 20% after GH (P < 0.05) and 56% after GH + testosterone (P = 0.0003). These data demonstrate sexually dimorphic IGFBP responses to GH. Additionally, HRT attenuated or prevented GH-mediated increases in IGF-I and IGFBP-3. Whether GH and/or sex steroid administration alters local tissue production of IGFBPs and whether the latter influence autocrine or paracrine actions of IGF-I remain to be determined.     

Effect of medical castration on CD4+ CD25+ T cells, CD8+ T cell IFN-gamma expression, and NK cells: a physiological role for testosterone and/or its metabolites

The higher prevalence of autoimmune disease among women compared with men suggests that steroids impact immune regulation. To investigate how sex steroids modulate cellular immune function, we conducted a randomized trial in 12 healthy men aged 35-55 yr treated for 28 days with placebo, a GnRH antagonist, acyline to induce medical castration, or acyline plus daily testosterone (T) gel to replace serum T, followed by a 28-day recovery period. Serum hormones were measured weekly and peripheral blood lymphocytes (PBLs) were collected biweekly for analyses of thymus-derived lymphocyte (T cell) subtypes and natural killer (NK) cells. Compared with the other groups and to baseline throughout the drug exposure period, men receiving acyline alone had significant reductions in serum T (near or below castrate levels), dihydrotestosterone, and estradiol (P < 0.05). Medical castration significantly reduced the percentage of CD4+ CD25+ T cells (P < 0.05), decreased mitogen-induced CD8+ T cell IFN-gamma expression, and increased the percentage of NK cells without affecting the ratio of CD4+ to CD8+ T cells and the expression of NK cell-activating receptor NKG2D or homing receptor CXCR1. No changes in immune composition were observed in subjects receiving placebo or acyline with replacement T. These data suggest that T and/or its metabolites may help maintain the physiological balance of autoimmunity and protective immunity by preserving the number of regulatory T cells and the activation of CD8+ T cells. In addition, sex steroids suppress NK cell proliferation. This study supports a complex physiological role for T and/or its metabolites in immune regulation.     

Increased memory load-related frontal activation after estradiol treatment in postmenopausal women

Prior research shows that menopause is associated with changes in cognition in some older women. However, how estrogen loss and subsequent estrogen treatment affects cognition and particularly the underlying brain processes responsible for any cognitive changes is less well understood. We examined the ability of estradiol to modulate the manipulation of information in working memory and related brain activation in postmenopausal women. Twenty healthy postmenopausal women (mean age (SD) = 59.13 (5.5)) were randomly assigned to three months of 1 mg oral 17-β estradiol or placebo. At baseline and three months later each woman completed a visual verbal N-back sequential letter test of working memory during functional magnetic resonance imaging (fMRI). The fMRI data showed that women who were treated with estradiol for three months had increased frontal activation during the more difficult working memory load conditions compared to women treated with placebo. Performance on the verbal working memory task showed no difference between estradiol and placebo treated subjects. These data are consistent with prior work showing increases in frontal activation on memory tasks after estrogen treatment. However, this is the first study to show that estrogen-induced increases in brain activity were tied to cognitive load during a verbal working memory task. These data suggest that estradiol treatment effects on cognition may be in part produced through modulation of frontal lobe functioning under difficult task conditions.     

Are optimal levels of testosterone associated with better cognitive function in healthy older women and men?

Background

Sex steroids can positively affect the brain and from this it would follow that high levels of sex steroids could be associated with better cognitive function in older men and women.

Methods

This Healthy Ageing Study sample comprised of 521 older participants (51% women) without dementia at baseline, with an age range from 64 to 94 years. Testosterone and sex hormone binding globulin were measured using the automated Immulite 2000 and analyzed in association with baseline memory, global cognitive function and decline (assessed using the Mini-Mental Status Examination or MMSE) and controlling for potential confounds such as age, education, vascular disease, smoking, diabetes, thyroid function, and body mass index.

Results

In healthy older men and women, optimal levels of testosterone were associated with better MMSE scores at baseline. Follow-up analyses indicated that in men, low testosterone levels (OR = .94, 95% CI = .88 to 1.00) were a risk factor for a sharp cognitive decline after 2 years, perhaps indicative of dementia. Associations were independent of covariates and baseline MMSE. Conversely, women at risk for a sharp drop in cognitive function showed some evidence for higher calculated free testosterone levels at baseline.

Conclusions

Results replicate earlier cross-sectional findings that high levels of sex steroids are not associated with better cognitive function in older people. In men, age accelerated endocrinological change could be associated with dementia pathology.

General significance

These data do not support increasing testosterone levels to prevent cognitive decline in men and women over 65 years of age.     

Effects of testosterone and estradiol on cutaneous vasodilation during local warming in older men

Microvascular vasodilation in humans can become impaired with age, leading to cardiovascular diseases ranging from mild to life-threatening. Reproductive hormones may confer some protection on the vascular system in women; however, it is unclear whether the same is true in men. Our goal was to evaluate the impact of four hormonal conditions (testosterone only, estradiol only, testosterone and estradiol, no testosterone and no estradiol) on microvascular vasodilator responsiveness in the skin of older men. We hypothesized that in older healthy men estradiol promotes cutaneous microvascular dilation during local warming of the skin and that testosterone inhibits this dilation. We measured skin blood flow using laser Doppler flowmetry during 35 min of cutaneous local warming to 42 degrees C in 52 healthy men (average age 67 +/- 1 yr). Subjects were randomized to one of the four hormonal conditions and were studied before and after hormone treatments. The endothelium-dependent vasodilator response to local warming was not different among groups either before or after hormone treatment. For example, with testosterone-only treatment this vasodilator response was 220 +/- 13 AU, and with estrogen only the response averaged 246 +/- 12 AU (P > 0.05). We conclude that, within the doses employed in the present study, testosterone and estradiol did not consistently alter cutaneous vasodilator responsiveness in healthy older men.     

Sympathetic neural responses to 24-hour sleep deprivation in humans: sex differences

Sleep deprivation has been linked to hypertension, and recent evidence suggests that associations between short sleep duration and hypertension are stronger in women. In the present study we hypothesized that 24 h of total sleep deprivation (TSD) would elicit an augmented pressor and sympathetic neural response in women compared with men. Resting heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) were measured in 30 healthy subjects (age, 22 ± 1; 15 men and 15 women). Relations between spontaneous fluctuations of diastolic arterial pressure and MSNA were used to assess sympathetic baroreflex function. Subjects were studied twice, once after normal sleep and once after TSD (randomized, crossover design). TSD elicited similar increases in systolic, diastolic, and mean BP in men and women (time, P < 0.05; time × sex, P > 0.05). TSD reduced MSNA in men (25 ± 2 to 16 ± 3 bursts/100 heart beats; P = 0.02), but not women. TSD did not alter spontaneous sympathetic or cardiovagal baroreflex sensitivities in either sex. However, TSD shifted the spontaneous sympathetic baroreflex operating point downward and rightward in men only. TSD reduced testosterone in men, and these changes were correlated to changes in resting MSNA (r = 0.59; P = 0.04). Resting HR, respiratory rate, and estradiol were not altered by TSD in either sex. In conclusion, TSD-induced hypertension occurs in both sexes, but only men demonstrate altered resting MSNA. The sex differences in MSNA are associated with sex differences in sympathetic baroreflex function (i.e., operating point) and testosterone. These findings may help explain why associations between sleep deprivation and hypertension appear to be sex dependent.     

Complex regulation of GH autofeedback under dual-peptide drive: studies under a pharmacological GH and sex steroid clamp

To test the postulate that sex difference, sex steroids, and peptidyl secretagogues control GH autofeedback, 11 healthy postmenopausal women and 14 older men were each given 1) a single iv pulse of GH to enforce negative feedback and 2) continuous iv infusion of saline vs. combined GHRH/GHRP-2 to drive feedback escape during pharmacological estradiol (E(2); women) or testosterone (T; men) supplementation vs. placebo in a double-blind, prospectively randomized crossover design. By three-way ANCOVA, sex difference, sex hormone treatment, peptide stimulation, and placebo/saline responses (covariate) controlled total (integrated) GH recovery during feedback (each P < 0.001). Both sex steroid milieu (P = 0.019) and dual-peptide stimulation (P < 0.001) determined nadir (maximally feedback-suppressed) GH concentrations. E(2)/T exposure elevated nadir GH concentrations during saline infusion (P = 0.003), whereas dual-peptide infusion did so independently of T/E(2) and sex difference (P = 0.001). All three of sex difference (P = 0.001), sex steroid treatment (P = 0.005), and double-peptide stimulation (P < 0.001) augmented recovery of peak (maximally feedback-escaped) GH concentrations. Peak GH responses to dual-peptidyl agonists were greater in women than in men (P = 0.016). E(2)/T augmented peak GH recovery during saline infusion (P < 0.001). Approximate entropy analysis corroborated independent effects of sex steroid treatment (P = 0.012) and peptide infusion (P < 0.001) on GH regularity. In summary, sex difference, sex steroid supplementation, and combined peptide drive influence nadir, peak, and entropic measurements of GH release under controlled negative feedback. To the degree that the pharmacological sex steroid, GH, and dual-peptide clamps provide prephysiological regulatory insights, these outcomes suggest major determinants of pulsatile GH secretion in the feedback domain.     

Estradiol interacts with the cholinergic system to affect verbal memory in postmenopausal women: evidence for the critical period hypothesis

Estradiol has been shown to interact with the cholinergic system to affect cognition in postmenopausal women. This study further investigated the interaction of estradiol and cholinergic system functioning on verbal memory and attention in two groups of healthy younger (ages 50-62) and older (ages 70-81) postmenopausal women. Twenty-two postmenopausal women were randomly and blindly placed on 1 mg of 17-beta estradiol orally for 1 month then 2 mg for 2 months or matching placebo pills after which they participated in three anticholinergic challenge sessions when verbal memory and attention were assessed. Subjects were administered either the antimuscarinic drug scopolamine (SCOP), the antinicotinic drug mecamylamine (MECA), or placebo. After the first challenge phase, they were crossed over to the other hormone treatment for another 3 months and repeated the challenges. Results showed that estradiol pretreatment significantly attenuated the anticholinergic drug-induced impairments on a test of episodic memory (the Buschke Selective Reminding Task) for the younger group only, while estradiol treatment impaired performance of the older group. The results suggest that younger subjects may experience more cholinergic benefit from estradiol treatment than older subjects, supporting the concept of a critical period for postmenopausal estrogen use.     

Androgens and bone

Testosterone is the major gonadal sex steroid produced by the testes in men. Testosterone is also produced in smaller amounts by the ovaries in women. The adrenal glands produce the weaker androgens dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione. These androgens collectively affect skeletal homeostasis throughout life in both men and women, particularly at puberty and during adult life. Because testosterone can be metabolized to estradiol by the aromatase enzyme, there has been controversy as to which gonadal sex steroid has the greater skeletal effect. The current evidence suggests that estradiol plays a greater role in maintenance of skeletal health than testosterone, but that androgens also have direct beneficial effects on bone. Supraphysiological levels of testosterone likely have similar effects on bone as lower levels via direct interaction with androgen receptors, as well as effects mediated by estrogen receptors after aromatization to estradiol. Whether high doses of synthetic, non-aromatizable androgens may, in fact, be detrimental to bone due to suppression of endogenous testosterone (and estrogen) levels is a potential concern that warrants further study.     

Effects of Estrogen and Testosterone on Resting Energy Expenditure in Older Men

The mechanisms by which sex hormones cause changes in body composition are unclear. Sex steroid deficiency might directly reduce energy expenditure/fat oxidation and thereby predispose to increased body fat. Alternatively, sex steroid deficiency could result in lean tissue loss and thus reduced energy expenditure. Our objective was to examine the independent and combined effects of acute testosterone and estrogen withdrawal on respiratory exchange ratio (RER) and resting energy expenditure (REE) in men. The objective of the study was to examine the independent and combined effects of acute estrogen and testosterone withdrawal on RER and REE in men. A total of 54 men aged 50–80 years, BMI range of 17–35 kg/m² underwent a 3‐week eugonadal run‐in hormone‐treatment period involving suppression of endogenous sex steroids using letrozole and leuprolide acetate (Lupron) while sex steroid concentrations were maintained with transdermal testosterone (T) and estradiol (E). A second Lupron injection was then given and participants were randomized to one of the following four 3‐week treatment groups: group A (?T, ?E), group B (?T, +E), group C (+T, ?E), and group D (+T, +E). REE and RER were measured via indirect calorimetry before and after the 3‐week treatment period. Three‐week suppression and/or repletion of estrogen or testosterone did not produce changes in RER or REE within or between groups. We conclude that abrupt changes in sex steroids does not change resting substrate oxidation, indicating that changes that can be observed after more prolonged periods of deficiency are most likely due to direct effects of sex steroids on body composition.     

Oral contraceptives and cognition: A role for ethinyl estradiol

This article is part of a Special Issue "Estradiol and cognition".Estrogens have been seen to play a role in human cognitive abilities, but questions remain about the cognitive impact of ethinyl estradiol, which is contained in many oral contraceptives (OCs). Inconsistencies in past studies likely reflect small samples and heterogeneous groups of OC users. The aims of the present work were to examine OC effects on sex-typed spatial and verbal abilities by (a) comparing mental rotations and expressional fluency in normally-cycling (NC) women and men to OC users considered as a heterogeneous group and then to homogeneous groups of OC users created by classifying pills according to their active constituents, and (b) determining the relation between synthetic hormone doses in OCs and mental rotations and expressional fluency. Participants were 136 men, 93 NC women, and 148 OC users, including homogeneous monophasic (n = 55) and triphasic (n = 43) OC groups, aged 18 to 30 years. Significant effects of OC use were seen in homogeneous group comparisons but not when OC users were considered as a heterogeneous group. On mental rotations, men outperformed women, and monophasic OC users outperformed NC women. The latter difference may be attributable to estradiol, as ethinyl estradiol was inversely related to spatial ability among OC users and was lower in monophasic than in triphasic users. On expressional fluency, NC women and monophasic OC users outperformed men, and monophasic users outperformed triphasic users. Thus, results show the importance of ethinyl estradiol and of considering pill constituents when studying the cognitive effects of OCs.     

Effects of the pharmacologic manipulation of testosterone on cognitive functioning in women with polycystic ovary syndrome: a randomized, placebo-controlled treatment study

In a previous study, we found that women with polycystic ovary syndrome (PCOS), an endocrine disorder characterized by chronic hyperandrogenism, performed more poorly than healthy, matched controls on a number of neuropsychological tests, in particular tests of verbal fluency, verbal memory, manual dexterity, and visuospatial working memory. This randomized, placebo-controlled trial was undertaken to investigate whether pharmacologic manipulation of free testosterone (free T) levels in women with PCOS might affect their performance on cognitive tests. Nineteen women with PCOS completed a battery of neuropsychological tests before and after 3 months of treatment with either an anti-androgen (cyproterone acetate) plus estrogen or with a placebo. Hormone treatment of women with PCOS caused a significant reduction in their free T levels but did not affect performance on tests visuospatial ability, verbal memory, manual dexterity, or perceptual speed. Women treated with hormone therapy did, however, demonstrate an improvement in their performance on a test of verbal fluency compared to their pre-treatment scores. These findings suggest that changes in free T levels do not have a significant impact on cognitive performance in women with PCOS, although reductions in free T may be beneficial for verbal fluency.     

Interrelations and associations of serum levels of steroids and pituitary hormones with markers of insulin resistance,inflammatory activity,and renal function in men and women aged >70 years in an 8-year longitudinal study of opposite-sex twins

Background: The physiological serum levels of steroids and pituitary hormones in older men and women have been sparsely reported in the literature.Objectives: The aims of this study were to investigate the normal variation and sex differences in steroids and pituitary hormones in those aged >70 years, and to study the interrelation between these hormones and indicators of the metabolic syndrome, inflammatory activity, and renal function.Methods: The investigation comprised a population-based sample of pairs of white opposite-sex twins from the Swedish Twin Registry. At baseline in 1996 and at the 8-year follow-uup in 2004, serum levels of progesterone, cortisol, testosterone, estradiol, follicle-stimulating hormone, luteinizing hormone, prolactin, creatinine, C-reactive protein (CRP), and urea were analyzed. Serum levels of insulin and cystatin were analyzed only at the follow-up.Results: The study sample included 219 men and 183 women aged 71 to 80 years (mean [SD], 74.5 [2.5] years) at baseline in 1996, and 127 men and 135 women at follow-uup in 2004. At baseline, in both men and women, the variation of progesterone in serum was positively correlated with that of estradiol (men: r = 0.226, P < 0.01; women: r = 0.115, P = NS), testosterone (men: r = 0.178, P < 0.01; women: r = 0.315, P < 0.001), and cortisol (men: r = 0.314, P < 0.001; women: r = 0.296, P < 0.001). The values of progesterone and other steroid hormones were associated with markers of insulin resistance (iie, insulin, waist circumference), inflammatory activity (ie, CRP) for progesterone (men: r = 0.267, P < 0.001; women: r = 0.150, P < 0.05), and renal function (ie, creatinine) for progesterone (men: r = 0.424, P < 0.001; women: r = 0.212, P < 0.01). Estradiol and prolactin were associated with insulin resistance, inflammation, and renal function. Furthermore, progesterone was associated with prolactin (men: r = 0.275, P < 0.001; women: r = 0.172, P < 0.05).. Among both men and women, there was a strong correlation between testosterone and estradiol (men: r = 0.753, P < 0.001; women: r = 0.526, P < 0.001); in women, there was also a link between testosterone and cortisol at follow-up (r = 0.340, P < 0.01). For progesterone, there was a significant correlation between the values of the co-twins (in 1996: r = 0.16, P < 0.05; in 2004: r = 0.45, P < 0.001). Higher serum levels of progesterone (2.0 [0.7] nmol/L in men and 1.7 [0.8] nmol/L in women) and prolactin (6 [5] μg/L in men and 8 [10] μg/L in women) were found among those who were deceased at follow-up compared with survivors (progesterone: 1.8 [0.5] nmol/L in men and 1.4 [0.6] nmol/L in women, P < 0.01; prolactin: 4 [3] μg/L in men and 5 [2] μg/L in women, P < 0.001).Conclusions: In this study of opposite-sex Swedish twins aged >70 years, there was a sex difference in the serum levels of steroids and pituitary hormones between men and women. Progesterone and other steroid hormones were associated with markers of insulin resistance, inflammatory activity, and renal function. Progesterone and prolactin levels were associated with increased risk of mortality in this sample.     

Somatomedins and steroids

Somatomedin levels measured by radioreceptor assay, competitive protein-binding assay or radioimmunoassay are normal in hypercortisolism; the decrease of somatomedin activity consistently found in this condition is due to an increase in circulating somatomedin inhibitors resulting in an inhibition of somatomedin action. Progestagens could possibly have a direct stimulatory effect on somatomedin-C (Sm-C) production. During puberty, the increase of Sm-C is correlated with the increase in plasma estradiol and testosterone. In young subjects, relatively low doses of estrogens and of testosterone enhance Sm-C secretion, and in adult menstruating women, a positive relationship is found between testosterone and Sm-C values. An inhibitory effect of estrogens on Sm-C is observed with higher doses and/or in older subjects. Thus, somatomedin levels might be modulated by variations of sex steroids.     

Androgen treatment of male hypogonadism in older males

The treatment of primary and secondary hypogonadism with testosterone is well established. Recently, there has been increased awareness that low testosterone levels also occur in chronically ill persons and aging males. Because of sex hormone binding globulin changes, it is more appropriate to make the diagnosis using either free or bioavailable testosterone. A small number of controlled studies have suggested that testosterone replacement in older men improves libido, quality of erections, some aspects of cognition, muscle mass, muscles strength, and bone mineral density. It also decreases fat mass and leptin levels. A number of screening questionnaires for the andropause have been developed. Insufficient numbers of older men have been treated with testosterone to characterize the true incidence of side effects. There is a desperate need for well designed, large controlled trials to establish the value or otherwise of testosterone treatment in older males.