Body Stuff Androgens and Mood

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Androgens and Mood

: Plasma testosterone and dehydroepiandrosterone sulfate in male and female patients with dysthymic disorder.

Markianos M, Tripodianakis J, Sarantidis D, Hatzimanolis J.

Athens University Medical School, Psychiatric Clinic, Eginition Hospital, Vas. Sophias 74, Athens 11528, Greece.

BACKGROUND: Depressive symptomatology has been connected with an activation of the hypothalamus-pituitary-adrenal axis and, in several studies, with reduced androgen levels, while administration of androgens, usually in older subjects, may have positive effects on mood, both in males and females. Regarding dysthymic disorder (DD), low serum testosterone levels have been reported in older males, while information on younger male or on female patients is lacking. METHODS: We assessed the serum levels of testosterone (T), dehydroepiandrosterone sulfate (DHEAS) and cortisol in male and female patients with DD, and compared them to the levels of sex and age matched controls. Eighteen male and 43 female patients in the age range of 22 to 71 years were studied and diagnosed according to the Scheduled Diagnostic Interview for DSM-IV axis I disorders (SCID). Depressive symptomatology was assessed using the Hamilton Depression Rating Scale. Subgroups with subjects below or over 50 years of age were also built and compared. RESULTS: Serum T levels were lower than controls mainly in the subjects aged below 50 years, in both genders. More pronounced were reductions in DHEAS levels both in male and female patients, while cortisol levels were normal or reduced. T levels were positively correlated to both DHEAS and cortisol. The negative correlations of DHEAS and T to age were significant for all groups and subgroups, except in the group of male patients. Four male patients (22%) had T levels below 2.0 ng/ml. CONCLUSIONS: Male and female patients with DD aged below 50 years show reduced gonadal and adrenal androgen levels, and normal to low cortisol levels. These neuroendocrine characteristics differentiate DD from depression, and place this diagnostic group closer to posttraumatic stress disorder.

PMID: 17182106 [PubMed - as supplied by publisher]

: Testosterone and the brain.

Zitzmann M.

Institute of Reproductive Medicine, University of Munster, Munster, Germany. michael.zitzmann@ukmuenster.de

Gender differences in spatial recognition, and age-related declines in cognition and mood, point towards testosterone as an important modulator of cerebral functions. Testosterone appears to activate a distributed cortical network, the ventral processing stream, during spatial cognition tasks, and addition of testosterone improves spatial cognition in younger and older hypogonadal men. In addition, reduced testosterone is associated with depressive disorders. The relationship between depression and testosterone appears to partly depend upon the androgen receptor genotype of the patient, and in appropriate patients with low testosterone levels, testosterone substitution can increase positive mood and decrease negative mood. The much publicized link between testosterone and aggression is probably only of importance in athletes who supplement their testosterone levels to excessively high levels, whereas in hypogonadal men, testosterone supplementation only enhances the positive aspects of aggression such as vigour and energy. Current data suggest that testosterone supplementation in hypogonadal men of all ages will enhance many aspects of mood and cognition.

PMID: 17178554 [PubMed - in process]

3: J Steroid Biochem Mol Biol. 2006 Dec;102(1-5):195-204.

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Metabolism of exogenous sex steroids and effect on brain functions with a focus on tibolone.

Verheul HA, Kloosterboer HJ.

Research and Development, N.V. Organon, Oss, The Netherlands. herman.verheul@organon.com

Around the menopause, changes in ovarian secretion of steroids result in changes in brain function: hot flushes and sweating later followed by changes in mood, libido and cognition. The relationship between sex steroids and brain functions are reviewed, with focus on hormonal treatments, in particular tibolone, on the postmenopausal brain and on associations between tissue levels and brain functions. Data on steroid levels in human brain are limited. Exogenous oestrogens alone or combined with progestagens reduce hot flushes and sweating, and may favourably affect anxiety, depression and mood. Testosterone alone or combined with E(2) improves libido and mood. Tibolone reduces hot flushes and sweating, and improves mood and libido, but does not stimulate endometrium or breast, like oestrogens. Tibolone is an ideal compound for studying steroid levels and metabolism in brain in view of its structural differences from endogenous steroids and its extensive metabolism required to express its endocrine effects. Brain levels of tibolone metabolites were measured in ovariectomized cynomolgus monkeys receiving tibolone for 36 days. Compared to serum, higher levels of the oestrogenic 3alpha/beta-hydroxytibolone and the androgenic/progestagenic Delta(4)-tibolone, and lower levels of sulphated metabolites are found in various brain regions. The high levels of oestrogenic metabolites in the hypothalamus explain hot flush reduction. Combined with the presence of Delta(4)-tibolone, the tibolone-induced increase in free testosterone through SHBG reduction explains androgenic effects of tibolone on mood and libido. The levels of tibolone metabolites in the monkey brain support tibolone's effects on brain functions.

Publication Types:

Review

PMID: 17113982 [PubMed - indexed for MEDLINE]

4: Can J Psychiatry. 2006 Apr;51(5):295-9.

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Androgen treatment of depressive symptoms in older men: a systematic review of feasibility and effectiveness.

Shamlian NT, Cole MG.

Departement de psychiatrie, Service de psychogeriatrie, Hopital du Sacre-Coeur de Montreal, QC. medecins.clinique.memoire.hsc@ssss.gouv.qc.ca

OBJECTIVE: To determine the feasibility and effectiveness of androgen treatment of depressive symptoms in older men. METHOD: We searched MEDLINE, PsycINFO, Eric, HealthStar, and the Cochrane Database of Systematic Reviews for potentially relevant articles. The bibliographies of relevant articles were searched for additional references and experts were consulted. Seventeen reports (8 open and 12 randomized trials; 3 articles reported studies of 2 designs) met the following inclusion criteria: original investigation; published in English or French, use of acknowledged criteria or scale for depression, and open or randomized trial of androgen treatment. Four criteria assessed study validity: randomization, double blinding, comparability of treatment and control groups at baseline, and description of dropouts. We abstracted, tabulated, and compared information from each article. RESULTS: Most studies had methodological limitations. With regard to feasibility, there were few reported withdrawals due to adverse events. With regard to effectiveness, 6 of 8 open trials had positive results, and 5 of 12 randomized trials had positive results, although 1 was equivocal. However, testosterone was combined with antidepressant medication in 3 of these positive randomized trials. Only 2 open trials enrolled subjects whose mean age was 60 years or over. One had positive results, and the other had negative results. CONCLUSION: Androgen therapy may be feasible in the short term, but there is little evidence that it is an effective treatment for depressive symptoms in older men.

Publication Types:

Review

PMID: 16986819 [PubMed - indexed for MEDLINE]

5: J Endocrinol Invest. 2005;28(11 Suppl Proceedings):49-54.

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Partial androgen deficiency and neuropsychiatric symptoms in aging men.

Amore M.

Department of Neurosciences, Division of Psychiatry, University of Parma, 43100 Parma, Italy. mario.amore@unipr.it

The partial androgen deficiency of aging males (PADAM) is responsible for a variety of behavioral symptoms, such as weakness, fatigue, decreased libido, depressive mood, lack of motivation and energy, lower psychological vitality, anxiety, irritability, insomnia, decreased work and sport performances, difficulty in concentrating, memory impairment and low dominance. Psychological and behavioral aspects of PADAM overlap with signs and symptoms of major depression. The evidence of the association between testosterone (T) level and male depression comes from studies that have assessed: 1) depression in hypogonadal subjects; 2) the relationship between T level and male depressive illness, and 3) the antidepressant action of androgen replacement. In humans, the role of androgens has been described, albeit inconsistently, in the regulation of sexuality, aggression, emotion and personality. These direct effects appear to be greatly influenced by social factors as well. Sex hormones are important for the development and maintenance of acquired cognitive abilities. Hormonal changes in androgen levels in older men modulate, at least in part, the cognitive changes of aging. Treatment with androgen hormones in hypogonadal men has shown an improvement in cognitive, verbal and visual memory, mental status, visuomotor scanning and attention, verbal knowledge/language, spatial abilities and memory for both verbal and visual information. The etiology of the behavioral symptoms of PADAM is multifactorial, being the result of the interaction of biological and social changes, and of the personal ability to adapt to the numerous individual and social changes that take place during mid-life transition.

Publication Types:

Review

PMID: 16760626 [PubMed - indexed for MEDLINE]

: The male menopause and mood: testosterone decline and depression in the aging male -is there a link?

[No authors listed]

PMID: 16760038 [PubMed - in process]

7: Menopause. 2006 Jan-Feb;13(1):65-71.

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Endogenous androgen levels and well-being: differences between premenopausal and postmenopausal women.

Bell RJ, Donath S, Davison SL, Davis SR.

The Jean Hailes Foundation, Monash University, Clayton Victoria, Australia. womens.health@med.monash.edu.au

OBJECTIVE: We investigated whether there is a relationship between androgens levels and well-being in pre- and postmenopausal women. DESIGN: We randomly recruited 1423 women aged 18 to 75 years from the community via the electoral roll. Each provided a morning blood sample and completed the Psychological General Well Being Index questionnaire on the same day. Women were excluded if they took medication for any psychiatric illness, had abnormal thyroid function, or had documented polycystic ovarian syndrome. Analysis was by linear regression for well-being, including demographic and lifestyle variables as well as serum levels of androgens. RESULTS: We included 1224 women in the analysis. Being partnered was positively associated with well-being in premenopausal women. In postmenopausal women, well-being was positively related to age and exercising, whereas smoking, obesity, and postmenopausal hormone therapy use were each negatively associated with well-being. None of the measured androgens (total and free testosterone, dehydroepiandrosterone sulfate, and androstenedione) made an independent contribution to well-being in postmenopausal women (n = 603). However, for premenopausal women (n = 621), levels of dehydroepiandrosterone sulfate were independently and positively associated with the domain score for vitality. CONCLUSIONS: Our findings do not support an important independent role for androgens as determinants of well-being in postmenopausal women. That dehydroepiandrosterone sulfate alone is associated with greater vitality in premenopausal women is of interest but requires further evaluation as an a priori hypothesis in another study.

Publication Types:

Research Support, Non-U.S. Gov't

PMID: 16607100 [PubMed - indexed for MEDLINE]

8: Menopause. 2006 Jan-Feb;13(1):37-45.

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Comment in:

Effects of aromatase inhibition on sexual function and well-being in postmenopausal women treated with testosterone: a randomized, placebo-controlled trial.

Davis SR, Goldstat R, Papalia MA, Shah S, Kulkarni J, Donath S, Bell RJ.

Women's Health Program, Department of Medicine, Central and Eastern Clinical School, Monash University, Alfred Hospital, Prahran, Victoria, Australia. susan.davis@med.monash.edu.au

OBJECTIVE: The extent to which aromatization of testosterone (T) to estradiol is required for the observed effects of testosterone therapy on sexual function and well-being are not known. Therefore, the authors investigated the effects of aromatase enzyme inhibition on sexual function, well-being, and mood in estrogen- and T-replete postmenopausal women in a double-blind, randomized, placebo-controlled study. DESIGN: Postmenopausal women using transdermal estrogen therapy for at least 8 weeks and reporting low sexual satisfaction (score <42 for the Sabbatsberg Sexual Self-rating Scale [SSS]) with a total T value of less than 1.2 nmol/L were treated with 400 muL of a 0.5% T gel (total dose 2 mg) and were randomly assigned to receive treatment with either 2.5 mg/day of letrozole or an identical placebo tablet. Women were assessed at baseline (week -2) and at 0, 4, 8, and 16 weeks. Sexual function was assessed with the SSS, well-being was assessed with the Psychological General Well-being Index, and mood was assessed with the Beck Depression Inventory at 0 and 16 weeks. Eighty-one women were screened, 76 were randomly assigned to a treatment group, and 30 in each group completed the study. Because this was a mechanistic study, only the 60 women who completed the study per protocol were included in the final analysis. RESULTS: Total T and calculated free T increased from baseline in both groups, with no difference between groups. At 16 weeks, estradiol, sex hormone-binding globulin, fasting lipids, lipoprotein(a), and C-reactive protein did not differ from baseline or between groups. Significant increases in total Sabbatsberg Sexual Self-rating Scale scores, total Psychological General Well-being Index scores, and a reduction in Beck Depression Inventory scores from baseline to 16 weeks was seen for both treatment groups, with no effect of treatment allocation. No adverse treatment effects were reported. CONCLUSIONS: Increases in total and free T in the physiologic range in postmenopausal women were associated with improved sexual satisfaction, well-being, and mood. In this study, aromatase inhibition did not influence any of these outcomes. Short-term transdermal T therapy did not modify fasting lipids, lipoprotein(a), or C-reactive protein.

Publication Types:

PMID: 16607097 [PubMed - indexed for MEDLINE]

: Fluoxetine treatment and testosterone levels.

Bell S, Shipman M, Bystritsky A, Haifley T.

Private practice, Arcadia, CA, USA. sbellmd@hotmail.com

BACKGROUND: Two published case studies have reported SRI/SNRI-associated low testosterone levels. Apathy and low testosterone, observed during venlafaxine treatment in one report, both resolved upon venlafaxine discontinuation. No studies have investigated the effect of chronic SRI treatment on human testosterone levels.As decreased testosterone has several negative health effects, we conducted a pilot study investigating the effect of fluoxetine treatment on testosterone levels. METHODS: Fourteen depressive disorder patients in good health (BDI = 15) were studied. In addition, 4 non-depressed patients were studied. Testosterone levels were drawn, and an apathy questionnaire (under development, not yet validated) was administered at intake.Fluoxetine was provided (10 mg/day for 7 days then 20 mg/day). To measure outcome, a follow-up testosterone level was drawn after 1 month's treatment. RESULTS: Eleven depressed, and 3 non-depressed, patients completed the study. While there were large differences-both increases and decreases-in some individuals' testosterone levels after fluoxetine treatment, for the study population as a whole, there was no relationship (depressed patients, p = 0.4; non-depressed patients, p 0.3) between fluoxetine treatment and testosterone levels.In patients with BDI = 20, testosterone levels at intake were highly associated with intake apathy levels (p = 0.0033). CONCLUSIONS: Further, larger, studies correlating changes in testosterone levels during SRI treatment with treatment response, apathy levels and possibly sexual dysfunction seem indicated.

PMID: 16517449 [PubMed - indexed for MEDLINE]

10: J Clin Psychopharmacol. 2005 Dec;25(6):584-8.

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Intramuscular testosterone supplementation to selective serotonin reuptake inhibitor in treatment-resistant depressed men: randomized placebo-controlled clinical trial.

Seidman SN, Miyazaki M, Roose SP.

Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA. sns5@columbia.edu

BACKGROUND: Treatment-resistant depression is a persistent clinical problem. Exogenous testosterone therapy has psychotropic effects and has been proposed as an antidepressant supplement, although this strategy has received limited systematic study. OBJECTIVE: The aim of the study was to examine the mood effects of testosterone supplementation to a serotonergic antidepressant in men with treatment-resistant depression. METHOD: Twenty-six healthy adult men with major depressive disorder, partial or nonresponse to 2 adequate antidepressant trials during the current episode, and currently using a selective serotonin reuptake inhibitor were randomized under double-blind conditions to receive intramuscular injections of escalating doses of testosterone or placebo, in addition to their existing selective serotonin reuptake inhibitor regimen, for 6 weeks. The main outcome measure was the Hamilton Rating Scale for Depression score. RESULTS: The mean age was 46.4 +/- 10.8 years; mean total testosterone level, 417.5 +/- 197 ng/dL; mean baseline Hamilton Rating Scale for Depression score, 22.2 +/- 5.2; and median duration of the current depressive episode, 6.3 +/- 10.6 years. Hamilton Rating Scale for Depression scores decreased significantly in both testosterone (8.4) and placebo (7.4) groups. Antidepressant response, defined as a 50% decline in Hamilton Rating Scale for Depression score, was achieved by 53.8% (7/13) in the testosterone group and 23.1% (3/13) in the placebo group (P = 0.226). CONCLUSION: Both injectable testosterone and placebo supplementation to selective serotonin reuptake inhibitor were associated with improvement in mood; group differences were not distinguishable in this small sample of predominantly eugonadal men with treatment-resistant depression.

Publication Types:

Randomized Controlled Trial

PMID: 16282843 [PubMed - indexed for MEDLINE]

11: J Neuropsychiatry Clin Neurosci. 2005 Summer;17(3):372-7.

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Administration of testosterone increases functional connectivity in a cortico-cortical depression circuit.

Schutter DJ, Peper JS, Koppeschaar HP, Kahn RS, van Honk J.

Helmholtz Research Institute, Affective Neuroscience Section, Utrecht University, Heidelberglaan 2, 3584 CS Utrecht, the Netherlands. D.Schutter@fss.uu.nl

Increasing evidence suggests that the steroid hormone testosterone (T) enhances libido and decreases depression. Even a single administration of T (0.5 mg sublingually) in healthy young women is sufficient to enhance physiological sexual responsiveness. Such physiological evidence is not yet available for the link between T and depression. Recent research has revealed that lowered functional connectivity in a specific cortico-cortical pathway may be a sensitive physiological index for depression. This pathway, comprised of the left prefrontal and right parietal cortex, has been named a cortical depression circuit. In the present study, a single dose of T was administered to healthy young women to investigate the effects on the functional connectivity in this cortico-cortical depression circuit. It was hypothesized that administration of T would lead to an increase of functional connectivity. In a double-blind placebo-controlled, crossover design, fourteen healthy females received (sublingually) a single dose of 0.5 mg T or placebo in a randomly assigned fashion. Three hours after drug administration the functional coupling between the left prefrontal and right parietal cortex was established by measuring the interhemispheric electroencephalogram (EEG) coherence for the different frequency bands. Compared to placebo, T administration significantly increased the functional connectivity in the sigma (1-3 Hz) frequency range between the left prefrontal and right parietal cortex. Reductions in interhemispheric coherence in the sigma frequency range have been observed in clinically depressed patients. Thus the present findings may provide a first insight into the neurobiological mechanism by which T decreases depression. The fact that only a single dose of T was able to induce the effect in healthy female subjects suggests that the mechanism is highly sensitive. A feasible application of T treatment in the struggle against depression is discussed.

Publication Types:

PMID: 16179660 [PubMed - indexed for MEDLINE]

12: J Clin Endocrinol Metab. 2005 Aug;90(8):4836-45. Epub 2005 Apr 19.

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Comment in:

J Clin Endocrinol Metab. 2005 Aug;90(8):4970-2.

Correlates of circulating androgens in mid-life women: the study of women's health across the nation.

Santoro N, Torrens J, Crawford S, Allsworth JE, Finkelstein JS, Gold EB, Korenman S, Lasley WL, Luborsky JL, McConnell D, Sowers MF, Weiss G.

Division of Reproductive Endocrinology, Department of Obstetrics, Gynecology and Women's Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Mazer 316, Bronx, New York 10461, USA. glicktoro@aol.com

CONTEXT: Androgens influence sexual differentiation and behavior, body composition, and physical functioning in men, but their role in women is less well understood. Because circulating androgens decline with age, the use of androgen supplementation for women to improve health and well-being has been increasing. OBJECTIVE: The aim of this study was to assess the association between androgens and a variety of end points thought to be affected by androgens. DESIGN: In a community-based baseline cohort of women aged 42-52 yr from the Study of Women's Health Across the Nation, we measured circulating testosterone (T), dehydroepiandrosterone sulfate, and SHBG, and calculated a free androgen index (FAI) in 2961 women. MAIN OUTCOME MEASURES: Correlations of androgen measures with each other and with body mass index, waist circumference, and waist-hip ratio were computed, and odds ratios (OR) were estimated for the categorical outcomes of functional limitations, functional status, self-reported health, scores indicative of depressed mood, quality of life, sexual desire and arousal, and the presence of the metabolic syndrome. RESULTS: Androgens, and particularly SHBG, were associated most strongly with body mass index, waist circumference, and waist-hip ratio. SHBG was associated prominently inversely with the metabolic syndrome (OR = 0.32; 95% confidence interval = 0.26-0.39), which was present in 17% of women at baseline. Dehydroepiandrosterone sulfate was associated modestly with functional status and self-reported health. T was associated minimally with increased sexual desire (OR = 1.09; 95% confidence interval = 1.00-1.18). The association of FAI with self-reported health and depressive symptomatology based on the Center for Epidemiologic Studies Depression Scale score was explained more by T than by SHBG, whereas the association of FAI with sexual arousal and metabolic syndrome was due more to SHBG than to T. CONCLUSIONS: Circulating SHBG and androgens are most strongly associated with physical characteristics and the metabolic syndrome in women in this community-based cohort. Androgens are related weakly to physical functioning and other symptoms to which they commonly are attributed, such as sexual desire, sexual arousal, and well-being.

Publication Types:

PMID: 15840738 [PubMed - indexed for MEDLINE]

13: Climacteric. 2004 Dec;7(4):338-46.

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Hormones and depression in women.

Studd J, Panay N.

Chelsea & Westminster Hospital, London, UK.

The biological plausibility for the effect of sex hormones on the central nervous system is now supported by a considerable amount of clinical data. This critical review guides the reader through the plethora of data, from the earliest reports of menstrual madness in the nineteenth century to neurobiological work in the new millennium. It illustrates through the scientific evidence base that, although the effect of estrogen on the central nervous system, particularly on mood and depression, remains a controversial area, there is now considerable evidence for the psychotherapeutic benefits of estrogens in the triad of hormone-responsive depressive disorders: postnatal depression, premenstrual depression and perimenopausal depression. The article also reviews the compelling data that testosterone supplementation has positive effects for depression, libido and energy, particularly where patients have only partially responded to estrogen therapy.

Publication Types:

Review

PMID: 15799605 [PubMed - indexed for MEDLINE]

14: Treat Endocrinol. 2005;4(2):95-114.

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The use of dehydroepiandrosterone therapy in clinical practice.

Cameron DR, Braunstein GD.

Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.

Dehydroepiandrosterone (DHEA) therapy is controversial due to sensationalized reports of epidemiologic studies and the over-the-counter availability of DHEA. Human clinical trials have investigated the potential efficacy of DHEA therapy in multiple conditions with resultant inconsistencies in findings. DHEA is unique compared with other adrenal steroids because of the fluctuation in serum levels found from birth into advancing age. The lower endogenous levels of DHEA and DHEA sulfate found in advancing age have been correlated with a myriad of health conditions. Also, some studies suggest gender-specific actions of endogenous and exogenous DHEA.We reviewed only pharmacokinetic studies and human clinical trials investigating the efficacy of DHEA therapy that were placebo-controlled as these provided the most reliable scientific basis for the evaluation of DHEA therapy. Pharmacodynamic studies suggest that doses of 30-50mg of oral DHEA may produce physiologic androgen levels, especially in women. These studies report a dose-dependent effect and lack of accumulation of serum androgen levels. Pharmacologic studies also reveal a gender-specific response to DHEA therapy such that testosterone levels are increased in women but not in men.Clinical trials suggest that 50mg of oral DHEA, but not <30mg, can increase serum androgen levels to within the physiologic range for young adults with primary and secondary adrenal insufficiency, possibly improve sexual function, improve mood and self-esteem, and decrease fatigue/exhaustion. Whereas DHEA replacement therapy may be effective in treating patients with adrenal insufficiency, human clinical trials investigating its efficacy in conditions such as systemic lupus erythematosus, HIV, Alzheimer disease, advancing age, male sexual dysfunction, perimenopausal symptoms, depression, and cardiovascular disease have not provided consistent findings.

Publication Types:

Review

PMID: 15783247 [PubMed - indexed for MEDLINE]

15: J Geriatr Psychiatry Neurol. 2005 Mar;18(1):20-4.

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Safety and efficacy of testosterone gel 1% augmentation in depressed men with partial response to antidepressant therapy.

Orengo CA, Fullerton L, Kunik ME.

Veterans Affairs Medical Center, Houston, TX 77401, USA. corengo@bcm.tmc.edu

The current study evaluates the efficacy and safety of testosterone (T) gel 1% augmentation on depressive symptoms and quality of life in treatment-resistant, depressed, hypogonadal men older than 50 years of age who are receiving antidepressants. The authors hypothesized that T augmentation would improve depressive symptoms and quality of life. Eighteen hypogonadal men entered the study who had had an adequate trial of antidepressant therapy and had significant depressive symptoms. Participants were continued on their antidepressant and were randomized to receive either placebo or active T gel (5 g) to be applied once a day. Participants were tested on 6 occasions: screening visit, an initial session (pretreatment), at 6 and 12 weeks during the first treatment condition, and at 18 and 24 weeks during the crossover condition. The authors found a significant improvement in depressive symptoms from baseline to 12 weeks of testosterone treatment. However, a statistical difference between placebo and testosterone treatment phases was not demonstrated. The limitations of the study, including the chronicity and severity of patients' depression, variability in T levels, and a small sample size, probably influenced the ability to detect a discernable difference. Nevertheless, the study shows that T gel augmentation may be helpful in hypogonadal males with depression.

Publication Types:

PMID: 15681624 [PubMed - indexed for MEDLINE]

16: J Clin Endocrinol Metab. 2005 Mar;90(3):1428-33. Epub 2004 Dec 21.

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Testosterone administration in women with anorexia nervosa.

Miller KK, Grieco KA, Klibanski A.

Neuroendocrine Unit, BUL 457B, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. kkmiller@partners.org

Anorexia nervosa (AN) is complicated by severe bone loss, cognitive function deficits, and a high prevalence of major depression. We hypothesized that bone formation would increase and depressive symptoms and spatial cognition would improve with short-term physiological testosterone administration. We randomized 33 women with AN and relative testosterone deficiency to transdermal testosterone (Intrinsa, Procter and Gamble Pharmaceuticals, Cincinnati, OH), 150 mug, 300 mug, or placebo, for 3 wk. At baseline, free testosterone correlated with L4 bone density (r = 0.51, P < 0.001), body mass index (r = 0.39, P = 0.02), depressive symptoms (r = -0.44, P = 0.02), and spatial cognition (r = 0.45, P = 0.04). C-terminal propeptide of type 1 collagen levels were higher during testosterone administration than placebo (P = 0.03). The change in propeptide of type 1 collagen correlated with change in free testosterone over 3 wk (r = 0.50, P = 0.02). Osteocalcin and bone-specific alkaline phosphatase did not change. Depressed patients receiving testosterone improved from severely depressed to moderately depressed; the placebo group was unchanged (P = 0.02). Spatial cognition improved in the testosterone group, compared with placebo (P = 0.0015). Therefore, short-term low-dose testosterone may improve depressive symptoms and spatial cognition in women with AN. Low-dose testosterone may also prevent decreased bone formation in AN, but because testosterone did not affect all markers of bone formation studied, further data are needed.

Publication Types:

PMID: 15613421 [PubMed - indexed for MEDLINE]

17: Pol J Pharmacol. 2004 Sep-Oct;56(5):509-18.

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Neuroprotective role of testosterone in the nervous system.

Bialek M, Zaremba P, Borowicz KK, Czuczwar SJ.

Department of Pathophysiology, Skubiszewski Medical University, Jaczewskiego 8, PL 20-090 Lublin, Poland.

Testosterone -- the gonadal sex steroid hormone plays an important role in the central nervous system (CNS) development. One of the less known testosterone actions is neuroprotection. There are some evidences supporting the hypothesis that testosterone may act protectively in neurodegenerative disorders, e.g. Alzheimer's disease (AD), mild cognitive impairment (MCI) or depression. Androgens alter also the morphology, survival and axonal regeneration of motor neurons. These hormones accelerate the regeneration of hamster facial nerve and anterior tibialis sciatic nerve in rabbits following crush axotomy. Androgens exert trophic action in laryngeal motor nucleus of Xenopus laevis. Testosterone is linked to an increase in neuron somal size, neuritic growth, plasticity and synaptogenesis in both motoneurons of the spinal nucleus of the bulbocavernosus and several populations of pelvic autonomic neurons. The hormone reduced the extent of spinal cord damage in vitro. There are also evidences against the neuroprotective action of testosterone. Testosterone does not protect against methamphetamine-induced neurotoxicity of the dopaminergic system in mice and does not provide significant neuroprotection against glutamate-induced neurotoxicity. Androgens do not prevent striatal dopamine depletion induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. Although the role of testosterone in the CNS is still poorly understood, accumulating evidence suggests that testosterone may create a future treatment for MCI and related cognitive diseases, including dementia and may influence motor neuron regeneration in adulthood. Androgen replacement therapy in selected male populations may hold therapeutic promise for the prevention and/or treatment of age-related disorders associated with neuronal injury.

Publication Types:

Review

: Testosterone supplementation: what and how to give.

Jockenhovel F.

Medical Department, Evangelisches Krankenhaus Herne, Wiescherstrasse 24, 44623 Herne, Germany.

Several epidemiological studies have demonstrated a gradual decrease of serum testosterone with aging in men. A considerable number of men will experience hypogonadal androgen levels, defined by the normal range for young men. Thus, in addition to the long-standing use of androgen replacement therapy in the classical forms of primary and secondary hypogonadism, age-associated testosterone deficiency has led to considerable developments in application modes for testosterone. Since oral preparations of testosterone are ineffective, due to the first-pass effect of the liver, or, in case of 17 alpha-alkylation, cause hepatotoxicity, intramuscular injection of long-acting esters, such as testosterone enanthate, have been the mainstay of testosterone therapy. However, the large fluctuations of serum testosterone levels cause unsatisfactory shifts of mood and sexual function in some men; combined with the frequent injections, this delivery mode is thus far from being ideal. In contrast, the transdermal testosterone patches are characterized by favorable pharmacokinetic behavior and have proven to be an effective mode of delivery. Safety data over 10 years indicate no negative effect on the prostate. Nevertheless, the scrotal testosterone patch system is hampered by the application site, which is not easily accepted by many subjects; the non-scrotal patch has a high rate of skin irritations. In view of the drawbacks of the currently available preparations, the most recent developments in testosterone supplementation appear to be highly promising agents. Androgen, which has been available in the United States since mid-2000, will be introduced this year in most European markets as Testogel, a hydroalcoholic gel containing 1% testosterone. Doses of 50-100 mg gel applied once daily on the skin deliver sufficient amounts of testosterone to restore normal hormonal values and to correct the signs and symptoms of hypogonadism. The gel has shown to be very effective and successful in American patients, who have benefited from its availability for almost 3 years. Furthermore, in phase II and III clinical studies, the intramuscular injection of 1000 mg testosterone undecanoate every 12-15 weeks has led to extremely stable serum testosterone levels for a prolonged period of time and has resulted in excellent efficacy. It is very likely in the future that these products will be the mainstay of testosterone supplementation. Whereas the indication for testosterone substitution for men with classical forms of hypogonadism is unequivocal, the use of testosterone in men with age-associated hypogonadism is less uniformly accepted. Yet, the few studies addressing this question indicate that men with testosterone serum levels below the lower normal limit for young adult men and with lack of energy, libido, depressed mood and osteoporosis may benefit from testosterone supplementation. However, it should be kept in mind that the experience documented in studies is limited. Nevertheless, serious side-effects, especially in regard to the prostate, did not occur, with the longest study extending over 3 years.

PMID: 14628500 [PubMed - indexed for MEDLINE]

2: J Clin Endocrinol Metab. 1992 Dec;75(6):1503-7.

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The effects of exogenous testosterone on sexuality and mood of normal men.

Anderson RA, Bancroft J, Wu FC.

Medical Research Council Reproductive Biology Unit, Centre for Reproductive Biology, Edinburgh, Scotland.

The effects of supraphysiological levels of testosterone, used for male contraception, on sexual behavior and mood were studied in a single-blind, placebo-controlled manner in a group of 31 normal men. After 4 weeks of baseline observations, the men were randomized into two groups: one group received 200 mg testosterone enanthate (TE) weekly by im injection for 8 weeks (Testosterone Only group), the other received placebo injections once weekly for the first 4 weeks followed by TE 200 mg weekly for the following 4 weeks (Placebo/Testosterone group). The testosterone administration increased trough plasma testosterone levels by 80%, compatible with peak testosterone levels 400-500% above baseline. Various aspects of sexuality were assessed using sexuality experience scales (SES) questionnaires at the end of each 4-week period while sexual activity and mood states were recorded by daily dairies and self-rating scales. In both groups there was a significant increase in scores in the Psychosexual Stimulation Scale of the SES (i.e. SES 2) following testosterone administration, but not with placebo. There were no changes in SES 3, which measures aspects of sexual interaction with the partner. In both groups there were no changes in frequency of sexual intercourse, masturbation, or penile erection on waking nor in any of the moods reported. The Placebo/Testosterone group showed an increase in self-reported interest in sex during testosterone treatment but not with placebo. The SES 2 results suggest that sexual awareness and arousability can be increased by supraphysiological levels of testosterone. However, these changes are not reflected in modifications of overt sexual behavior, which in eugonadal men may be more determined by sexual relationship factors. This contrasts with hypogonadal men, in whom testosterone replacement clearly stimulates sexual behavior. There was no evidence to suggest an alteration in any of the mood states studied, in particular those associated with increased aggression. We conclude that supraphysiological levels of testosterone maintained for up to 2 months can promote some aspects of sexual arousability without stimulating sexual activity in eugonadal men within stable heterosexual relationships. Raising testosterone does not increase self-reported ratings of aggressive feelings.

PIP: Testosterone is necessary, though not sufficient for normal levels of sexual desire. Researchers are currently investigating the potential role of supraphysiological doses of testosterone as an hormonal contraceptive for men. This paper reports findings from such a study of the effects of supraphysiological levels of testosterone upon sex behavior and mood in 31 men. A single-blind, placebo-controlled study design was employed. The men were aged 21-41 years, healthy, and in stable heterosexual relationships. All subjects were normal on clinical examination, and their plasma testosterone and gonadotropins were within the normal range. Baseline data were gathered on the subjects over a four-week period of observation. The men were then randomized into two groups, men in one group receiving 200 mg testosterone enanthate (TE) weekly by intramuscular injection for eight weeks, and men in the other group receiving placebo injections once weekly for the first four weeks followed by TE 200 mg weekly for the following four weeks. Testosterone administration increased trough plasma testosterone levels by 80%, compatible with peak testosterone levels 400-500% above baseline. Various aspects of sexuality were assessed using sexuality experience scales (SES) questionnaires at the end of each four-week period, while sexual activity and mood states were recorded in daily dairies and self-rating scales. There was a significant increase in both groups in scores in the Psychosexual Stimulation Scale of the SES (SES 2) following testosterone administration, but not following receipt of placebo. There were no changes in the measurement of sexual interaction with the partner and no changes in either group in the frequency of sexual intercourse, masturbation, or penile erection on waking nor in any of the moods reported. The placebo/testosterone group showed an increased self-reported interest in sex during testosterone treatment, but not with placebo. SES 2 results suggest that sexual awareness and arousability can be increased by supraphysiological levels of testosterone. These changes, however, are not reflected in any change in overt sexual behavior, which in eugonadal men may be more determined by sexual relationship factors; this contrasts with hypogonadal men in whom testosterone replacement clearly stimulates sexual behavior. No evidence was found to suggest an alteration in any of the mood states studied, in particular those associated with increased aggression. The authors conclude that supraphysiological levels of testosterone maintained for up to two months can promote some aspects of sexual arousability without stimulating sexual activity in eugonadal men within stable heterosexual relationships.

Publication Types:

PMID: 1464655 [PubMed - indexed for MEDLINE]

: Testosterone substitution of hypogonadal men prevents the age-dependent increases in body mass index, body fat and leptin seen in healthy ageing men: results of a cross-sectional study.

Rolf C, von Eckardstein S, Koken U, Nieschlag E.

Institute of Reproductive Medicine of the University, Domagkstrasse 11, D-48129 Munster, Germany.

INTRODUCTION: In healthy men, body weight and total fat content increase with advancing age, while serum testosterone levels decrease. In order to elucidate whether a causal relationship between these phenomena exists, we investigated the influence of testosterone or human chorionic gonadotrophin substitution on body mass index (BMI), total fat mass and serum leptin in testosterone-treated and untreated hypogonadal patients in comparison with ageing eugonadal men. METHODS: In a cross-sectional study, the inter-relationships of body weight, total fat mass, serum sex hormones and leptin were analysed in untreated hypogonadal men (n=24; age 19-65 years), treated hypogonadal men (n=61; age 20-67 years) and healthy eugonadal men (n=60; age 24-78 years). Total fat mass was assessed by bioimpedance measurement. Univariate and multiple linear regression analysis was used to detect possible differences. RESULTS: In eugonadal men, serum testosterone levels decreased with advancing age (correlation coefficients: r=-0.71; P<0.0001), while BMI (r=0.39; P=0.002), total fat content (r=0.51; P<0.0001) and leptin (r=0.48; P<0.0001) increased significantly. In untreated hypogonadal patients, an increase in BMI (r=0.50; P=0.013) and total fat mass (r=0.41; P=0.044) was also observed with advancing age. However, in substituted hypogonadal patients, no age-dependent change in BMI (r=0.067; P=0.606), body fat content (r=-0.083; P=0.522), serum testosterone (r=-0,071; P=0.59) or serum leptin (r=-0.23; P=0.176) was found. CONCLUSION: Since testosterone-substituted older hypogonadal men show BMI and fat mass similar to those of younger eugonadal men and since non-treated hypogonadal men are similar to normal ageing men, testosterone appears to be an important factor contributing to these changes. Thus ageing men should benefit from testosterone substitution as far as body composition is concerned.

PMID: 11916618 [PubMed - indexed for MEDLINE]

4: J Endocrinol Invest. 2005;28(11 Suppl Proceedings):49-54.

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Review

PMID: 16760626 [PubMed - indexed for MEDLINE]

5: Physiol Behav. 2002 Apr 1;75(4):557-66.

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Exogenous testosterone, aggression, and mood in eugonadal and hypogonadal men.

O'Connor DB, Archer J, Hair WM, Wu FC.

Department of Endocrinology, Manchester Royal Infirmary, Manchester M13 9WL, UK. daryloc@psychology.leeds.ac.uk

To investigate (1) the effects of exogenous testosterone (T) on self- and partner-reported aggression and mood and (2) the role of trait impulsivity in the T-aggression relationship. Thirty eugonadal men with partners were randomized into two treatment groups to receive: (1) 200 mg im T enanthate weekly for 8 weeks or (2) 200 mg im sodium chloride weekly for 8 weeks. Eight hypogonadal men received 200 mg im T enanthate biweekly for 8 weeks. All groups completed a battery of behavior measures at baseline (Week 0) and at Weeks 4 and 8. Cognitive and motor impulsivity were the only predictors of self-reported total aggression (over and above age and T levels) at Weeks 0, 4, and 8. No significant changes in aggression or mood levels were found in the eugonadal-treated group. Significant reductions in negative mood (tension, anger, and fatigue) followed by an increase in vigor were found in response to T treatment in the hypogonadal group. These results demonstrate that inability to control one's behavior when such control is required by a particular situation (impulsivity) was found to significantly predict levels of aggression over and above age and T level. These data do not support the hypothesis that supraphysiological levels of T (within this range) lead to an increase in self- and partner-reported aggression or mood disturbances. Instead, for the first time, this study has identified the high level of negative affect experienced by hypogonadal patients. These findings have implications for T replacement therapy and male contraception.

Publication Types:

PMID: 12062320 [PubMed - indexed for MEDLINE]

6: Psychoneuroendocrinology. 2004 Jan;29(1):65-82.

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Relationship between testosterone supplementation and insulin-like growth factor-I levels and cognition in healthy older men.

Cherrier MM, Plymate S, Mohan S, Asthana S, Matsumoto AM, Bremner W, Peskind E, Raskind M, Latendresse S, Haley AP, Craft S.

Department of Psychiatry and Behavioral Sciences, University of Washington Medical School, 1959 NE Pacific, Box 356560, Seattle, WA 98195, USA. cherrier@u.washington.edu

BACKGROUND: Our laboratory has previously reported that testosterone (T) administration to older men significantly improves cognitive function. This study examined potential changes in insulin-like growth factor (IGF) IGF-I, IGF-II and IGF-related binding proteins in response to T administration in older men and their relationship to cognitive functioning. METHODS: Twenty-five healthy community dwelling volunteers, ranging in age from 50-80 years were randomized to receive weekly intra-muscular (i.m.) injections of either 100 mg T enanthate or placebo (saline) for 6 weeks. Serum hormone levels and cognitive functioning was assessed at baseline and twice during treatment. RESULTS: Significant positive associations between IGF-I and IGF-II and spatial memory, spatial reasoning, and verbal fluency were observed after 6 weeks of T administration. Increased serum T levels from treatment were positively associated with improvement in spatial reasoning performance, whereas estradiol was associated with a decline in divided attention performance. Serum IGF-I, IGF-II and IGFBPs did not change in response to T treatment. CONCLUSIONS: Our results suggest that T, estradiol and IGF-I may have independent and selective effects on cognitive functioning. Positive associations between T levels and cognition are consistent with an effect of androgen treatment, whereas positive associations between IGF-I levels and cognition are reflective of a relationship between endogenous IGF-I levels and cognition.

Publication Types:

PMID: 14575730 [PubMed - indexed for MEDLINE]

7: J Clin Endocrinol Metab. 1998 Dec;83(12):4251-6.

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Effects of androgen administration on the growth hormone-insulin-like growth factor I axis in men with acquired immunodeficiency syndrome wasting.

Grinspoon S, Corcoran C, Stanley T, Katznelson L, Klibanski A.

Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.

It is unknown whether hypogonadism contributes to decreased insulin-like growth factor I (IGF-I) production and/or how testosterone administration may effect the GH-IGF-I axis in human immunodeficiency virus (HIV)-infected men with the acquired immunodeficiency syndrome (AIDS) wasting syndrome (AWS). In this study, we investigate the GH-IGF-I axis in men with the AWS and determine the effects of testosterone on GH secretory dynamics, pulse characteristics determined from overnight frequent sampling, arginine stimulation, and total and free IGF-I levels. Baseline GH-IGF-I parameters in hypogonadal men with AWS (n=51) were compared before testosterone administration (300 mg, im, every 3 weeks vs. placebo for 6 months) with cross-sectional data obtained in two age-matched control groups: eugonadal men with AIDS wasting (n=10) and healthy age-matched normal men (n=15). The changes in GH-IGF-I parameters were then compared prospectively in testosterone- and placebo-treated patients. Mean overnight GH levels [1.8+/-0.3 and 2.4+/-0.3 vs. 0.90+/-0.1 microg/L (P=0.04 and P=0.003 vs. healthy controls)] and pulse frequency [0.35+/-0.06 and 0.37+/-0.02 vs. 0.22+/-0.03 pulses/h (P=0.06 and P=0.002 vs. healthy controls)] were comparably elevated in the eugonadal and hypogonadal HIV-positive groups, respectively, compared to those in the healthy control group. No significant differences in pulse amplitude, interpulse interval, or maximal GH stimulation to arginine administration (0.5 g/kg, i.v.) were seen between either the eugonadal and hypogonadal HIV-positive or healthy control patients. In contrast, IGF-I levels were comparably decreased in both HIV-positive groups compared to the healthy control group [143+/-16 and 165+/-14 vs. 216+/-14 microg/L (P=0.004 and P=0.02 vs. healthy controls)]. At baseline, before treatment with testosterone, overnight GH levels were inversely correlated with IGF-I (r=-0.42; P=0.003), percent ideal body weight (r=-0.36; P=0.012), albumin (r=-0.37; P=0.012), and fat mass (r=-0.52; P=0.0002), whereas IGF-I levels correlated with free testosterone (r=0.35; P=0.011) and caloric intake (r=0.32; P= 0.023) in the hypogonadal HIV-positive men. In a stepwise regression model, albumin (P=0.003) and testosterone (P=0.011) were the only significant predictors of GH [mean GH (microg/L)=-1.82 x albumin (g/dL) + 0.003 x total testosterone (microg/L) + 6.5], accounting for 49% of the variation in GH. Mean overnight GH levels decreased significantly in the testosterone-treated patients compared to those in the placebo-treated hypogonadal patients (0.9+/-0.3 vs. 0.2+/-0.4 microg/L; P=0.020). In contrast, no differences in IGF-I or free IGF-I were observed in response to testosterone administration. The decrement in mean overnight GH in response to testosterone treatment was inversely associated with increased fat-free mass (r=-0.49; P= 0.024), which was the only significant variable in a stepwise regression model for change in GH [change in mean GH (microg/L)=-0.197 x kg fat-free mass - 0.53] and accounted for 27% of the variation in the change in GH. In this study, we demonstrate increased basal GH secretion and pulse frequency in association with reduced IGF-I concentrations, consistent with GH resistance, among both hypogonadal and eugonadal men with AIDS wasting. Testosterone administration decreases GH in hypogonadal men with AIDS wasting. The change in GH is best predicted by and is inversely related to the magnitude of the change in lean body mass in response to testosterone administration. These data demonstrate that among hypogonadal men with the AWS, testosterone administration has a significant effect on the GH axis.

Publication Types:

Research Support, U.S. Gov't, P.H.S.

PMID: 9851759 [PubMed - indexed for MEDLINE]

: Gender Difference in Age-Related Number of Corticotropin-Releasing Hormone-Expressing Neurons in the Human Hypothalamic Paraventricular Nucleus and the Role of Sex Hormones.

Bao AM, Swaab DF.

Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.

Previous studies have shown that the total number of corticotropin-releasing hormone (CRH)-stained neurons in the human hypothalamic paraventricular nucleus (PVN) increases with age. To determine whether this age-related change depends on gender and whether circulating sex hormones play a role, we analyzed the total number of CRH-immunoreactive neurons by means of immunocytochemistry and image analysis in the postmortem hypothalamic PVN of 22 control subjects (11 males and 11 females) between the ages of 22 and 89 years, and of 10 subjects with abnormal sex hormone status. Our data show that men have a significantly larger number of CRH neurons than women (p = 0.004) and that the total number of CRH neurons increases significantly with age, but only in male controls (p = 0.032), not in female controls (p = 0.733). Female controls do not show a significant change in the total number of CRH neurons either before or after the age (50 years) of menopause (p = 0.792). Male subjects with low testosterone levels due to castration showed significantly fewer CRH neurons than well-matched intact males (p = 0.008), while castrated male-to-female (M-F) transsexuals with estrogen replacement showed normal numbers of CRH neurons. One male case, who had high estrogen levels due to an estrogen-producing tumor, showed a large number of CRH neurons. Thus, although circulating androgens and estrogens both seem to play a stimulatory role with respect to CRH neurons, the age-dependent increase in the number of CRH neurons in the PVN of men, which has been interpreted to reflect activation of the CRH neurons with age, seems to result from factors other than age-related changes of circulating sex hormone levels. Copyright (c) 2007 S. Karger AG, Basel.

PMID: 17308368 [PubMed - as supplied by publisher]

2: J Womens Health (Larchmt). 2006 Oct;15(8):898-908.

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Comment in:

J Womens Health (Larchmt). 2006 Oct;15(8):975-6.

Estrogen and androgen hormone therapy and well-being in surgically postmenopausal women.

Kotz K, Alexander JL, Dennerstein L.

Kotz Health Policy Consulting, Orinda, California 94563, USA. krista.kotz@kp.org

BACKGROUND: Women undergoing surgical menopause experience an abrupt drop in gonadal hormones and are more likely to have symptoms that negatively impact well-being, including hot flashes, sexual dysfunction, psychological problems, and testosterone deficiency. The purpose of this review was to examine the effects of hormone therapies on well-being among surgically menopausal women. METHODS: Studies were retrieved using both Cochrane and PubMed searches. A systematic literature review was performed to identify double-blind randomized controlled trials of the effects of menopausal hormone therapies on quality of life and well-being among women who have undergone hysterectomy with bilateral oophorectomy. Two studies meeting these criteria were included for review. RESULTS: For each study reviewed, the following aspects were examined: type of hormonal therapies used, inclusion/exclusion criteria, overall changes, and changes in specific parameters of well-being. General well-being improved from baseline with certain types and doses of estrogen or estrogen plus testosterone therapy, with no serious adverse events. CONCLUSIONS: Estrogen with or without testosterone may improve general well-being in some groups of surgically menopausal women. Levels of serum estrogen achieved in these studies were within a normal range for premenopausal women. Adding testosterone to estrogen therapy may provide additional improvements in well-being in some women, but only at supraphysiological levels of total testosterone and physiological levels of free testosterone. It is recommended that the clinician discuss the potential benefits and risks with each woman and devise an individualized plan based on shared decision making.

Publication Types:

PMID: 17087613 [PubMed - indexed for MEDLINE]

3: Clin Endocrinol (Oxf). 2006 Nov;65(5):673-80.

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Dehydroepiandrosterone (DHEA) replacement reduces growth hormone (GH) dose requirement in female hypopituitary patients on GH replacement.

Brooke AM, Kalingag LA, Miraki-Moud F, Camacho-Hubner C, Maher KT, Walker DM, Hinson JP, Monson JP.

Centre for Clinical Endocrinology, William Harvey Research Institute, St.Bartholomew's Hospital, QMUL, London, UK.

OBJECTIVE: GH dose requirement is lower in ACTH replete compared with ACTH deficient hypopituitary patients suggesting that adrenal androgens may augment IGF-I generation for a given GH dose. This study aimed to determine the effect of dehydroepiandrosterone (DHEA) administration on GH dose requirements in hypopituitary adults. DESIGN: A double blind placebo controlled trial was conducted adding 50 mg DHEA to the standard replacement of hypopituitary patients, including GH, over an initial 6 months, followed by an open phase study of 6 months DHEA replacement and a final 2 month washout phase after DHEA withdrawal. The dose of GH was adjusted to achieve a constant serum IGF-I. PATIENTS: Thirty female and 21 male hypopituitary patients were enrolled. Data from 26 women and 18 men were analysed after patient withdrawal. MEASUREMENTS: The primary outcome objective was the GH dose required to achieve a stable serum IGF-I. Secondary outcome measures were lipoprotein profiles, insulin, insulin sensitivity, IGFBP-3, waist/hip ratio and indices of bone remodelling. RESULTS: DHEA replacement in female patients lead to a 14.6 +/- 20% reduction in the dose of GH for a constant serum IGF-I (P < 0.05, 95% CI: 1.8, 32.7). This was maintained for 12 months and there was a significant fall in serum IGF-I two months after withdrawal of DHEA. There was no change in the male group. CONCLUSIONS: DHEA replacement may reduce GH dose requirements in female hypopituitary patients.

Publication Types:

Research Support, Non-U.S. Gov't

PMID: 17054472 [PubMed - in process]

4: J Clin Endocrinol Metab. 2006 Oct;91(10):3773-9. Epub 2006 Jul 18.

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Dehydroepiandrosterone improves psychological well-being in male and female hypopituitary patients on maintenance growth hormone replacement.

Brooke AM, Kalingag LA, Miraki-Moud F, Camacho-Hubner C, Maher KT, Walker DM, Hinson JP, Monson JP.

Department of Endocrinology, Harvey Research Institute, St. Bartholomew's Hospital, West Smithfield, London EC1A 7BE, United Kingdom.

CONTEXT: Patients with panhypopituitarism have impaired quality of life (QoL) despite GH replacement. They are profoundly androgen deficient, and dehydroepiandrosterone (DHEA) has been shown to have a beneficial effect on well-being and mood in patients with adrenal failure and possibly in hypopituitarism. OBJECTIVE: Our objective was to determine the effect of DHEA administration on mood in hypopituitary adults on established GH replacement with a constant serum IGF-I. DESIGN: A double-blind, placebo-controlled trial was conducted over an initial 6 months followed by an open phase of 6 months of DHEA. SETTING: The study was conducted at a tertiary referral endocrinology unit. PATIENTS: Thirty female and 21 male hypopituitary patients enrolled. Data from 26 females and 18 males were analyzed after patient withdrawal. INTERVENTIONS: DHEA (50 mg) was added to maintenance replacement including GH. MAIN OUTCOME MEASURES: The primary outcome objective was the effect on QoL and libido assessed by QoL assessment in GH deficiency in adults, Short Form 36, General Health Questionnaire, EuroQol, and sexual self-efficacy scale. RESULTS: Patients had impaired QoL at baseline compared with the age-matched British population. Females showed improvement in QoL assessment in GH deficiency in adults score (-2.9 +/- 2.8 DHEA vs.-0.53 +/- 3 placebo; P < 0.05), in Short Form 36 social functioning (14.6 +/- 23.1 DHEA vs.-4.7 +/- 25 placebo; P = 0.047), and general health perception (9.6 +/- 14.2 DHEA vs.-1.2 +/- 11.6 placebo; P = 0.036) after 6 months of DHEA. Men showed improvement in self-esteem (-1.3 +/- 1.7 DHEA vs. 0.5 +/- 1.5 placebo; P = 0.03) and depression (-1.6 +/- 2.2 DHEA vs. 1.2 +/- 2.4 placebo, P = 0.02) domains of the General Health Questionnaire after 6 months of DHEA. CONCLUSIONS: DHEA replacement leads to modest improvement in psychological well-being in female and minor psychological improvement in male hypopituitary patients on GH replacement.

Publication Types:

PMID: 16849414 [PubMed - indexed for MEDLINE]

5: Menopause. 2006 Jul-Aug;13(4):600-8.

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Testosterone aromatization and cognition in women: a randomized, placebo-controlled trial.

Shah S, Bell RJ, Savage G, Goldstat R, Papalia MA, Kulkarni J, Donath S, Davis SR.

NH and MRC Centre of Clinical Research Excellence in the Women's Health Program, Department of Medicine, Central and Eastern Clinical School, Monash University, Alfred Hospital, Prahran, Victoria, Australia.

OBJECTIVE: To explore whether inhibition of the conversion of testosterone to estradiol modifies the effects of testosterone on cognition in 61 healthy, estrogen-treated postmenopausal women. DESIGN: Seventy-six postmenopausal women using transdermal estrogen for at least 8 weeks, with a serum total testosterone less than 1.2 nmol/L participated in a single-center, double-blind, randomized, placebo-controlled study. All participants received transdermal testosterone, 400 muL of a 0.5% testosterone gel, daily and were randomized to receive either letrozole 2.5 mg/day or an identical placebo tablet. The main outcome measure was cognition, evaluated using a comprehensive battery of standardized neuropsychological tests, at baseline and week 16. RESULTS: Thirty women in each group completed the study. Free testosterone increased from baseline in both groups, with no difference between groups. Free testosterone levels achieved were below the 90th centile for young women in 80% of the participants at week 16. Serum estradiol and sex hormone-binding globulin levels did not differ from baseline or between groups during the study. No clinically significant effects of testosterone treatment were seen for attention and working memory, psychomotor speed, or executive function. Significant improvements were seen for immediate and delayed visual and verbal memory and for simple concentration with testosterone therapy, all of which were unaffected by the aromatase inhibitor. CONCLUSIONS: We did not observe any effects of aromatase inhibition on cognition in healthy, estrogen-treated postmenopausal women treated with testosterone. This may be due to insufficient study power or a true lack of effect. However, our findings highlight that the detection of subtle changes in cognition in well women require the development of sensitive instruments and large randomized, controlled trials.

Publication Types:

PMID: 16837882 [PubMed - indexed for MEDLINE]

6: Pharm Res. 2006 Jun;23(6):1117-32. Epub 2006 Jun 9.

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Testosterone hormone replacement therapy: state-of-the-art and emerging technologies.

Leichtnam ML, Rolland H, Wuthrich P, Guy RH.

School of Pharmaceutical Sciences, Faculty of Sciences, University of Geneva, CH-1211, Geneva 4, Switzerland.

In the human male, testosterone is the major circulating androgen. The clinical effects of androgen are numerous, and testosterone deficiency is associated with a number of clinical abnormalities. At present, a variety of preparations containing testosterone is available for the treatment of androgen deficiency. Ideally, those treatments have to produce and maintain physiologic serum concentrations of the hormone. This article reviews the current existing testosterone dosage forms on the market with their advantages and drawbacks and examines new and emerging technology developments concerning this therapy. In particular, the latest innovations in transdermal delivery are explored.

Publication Types:

Review

PMID: 16755346 [PubMed - indexed for MEDLINE]

: Does oral contraceptive-induced reduction in free testosterone adversely affect the sexuality or mood of women?

Graham CA, Bancroft J, Doll HA, Greco T, Tanner A.

Oxford Doctoral Course in Clinical Psychology, Isis Education Centre, Warneford Hospital, Oxford, England; The Kinsey Institute for Research in Sex, Gender, and Reproduction, Indiana University, Bloomington, IN, USA.

The aim of this study was to examine whether changes in plasma androgen levels (total testosterone (T), free testosterone (FT), and dehydro-epiandrosterone-sulfate (DHEA-S)) induced by oral contraceptive (OC) use were related to changes in sexual interest or response or in mood. Sixty-one women provided blood samples and were assessed, using interviews and standardized questionnaires, prior to starting, and after 3 months on OCs (Ortho-Tricyclen((R)), Ortho-Tricyclen-Lo((R)), or Ortho-Cyclen((R)), all containing the same progestagen, norgestimate). Significant decreases in T, FT, and DHEA-S were found after 3 months, although the extent of reduction was variable across women. There was some support for a relationship between the degree of reduction in total T and FT and the frequency of sexual thoughts after 3 months on OCs. However, some women had no loss of sexual interest in spite of substantial reduction in FT, and there was overall no evidence that reduction in FT affected enjoyment of sexual activity with a partner. The findings are consistent with the idea that some women may be more sensitive to changes in T than others. No relationship was found between negative mood, as assessed by the Beck Depression Inventory, and changes in T, FT, or DHEA-S.

PMID: 17314012 [PubMed - as supplied by publisher]

: Effects of dietary fat on androgen secretion and metabolism.

Gromadzka-Ostrowska J.

Warsaw Agricultural University, Faculty of Human Nutrition and Consuming Sciences, Department of Dietetic, Nowoursynowska 159C, 02-787 Warsaw, Poland. gromadzka@alpha.sggw.waw.pl.

In humans and animals, food composition, especially dietary fat, affects androgen secretion and metabolism. On the other hand, disturbances of sex steroid metabolism play an important role in the etiology of hormone-related cancers. In this report the roles of dietary fat, its quantity, fatty acid composition and feeding period on androgens metabolism was described. In conclusion, it should be stated that the amount of dietary fat, and its composition, (i.e. the content of individual fatty acids and/or their groups), as well as the period during which the nutrient is fed to animals affect significantly the secretion and metabolism of androgens.

PMID: 17220937 [PubMed - in process]

: DHEA therapy for women: effect on sexual function and wellbeing.

Panjari M, Davis SR.

NH&MRC Centre of Clinical Research Excellence in the Women's Health Program, Department of Medicine, Central and Eastern Clinical School, Monash University, Alfred Hospital, Prahran, Victoria, Australia.

DHEA is increasingly available commercially as a supplement aimed at improving libido and wellbeing in postmenopausal women. However there is scant evidence to support the use of DHEA for this purpose, and safety data for DHEA therapy are lacking.Dehydroepiandrosterone (DHEA) and its sulphate DHEAS are the most abundant circulating sex steroid hormones in women, providing a large precursor reservoir for the intracellular production of androgens and oestrogens in non-reproductive tissues. Levels of DHEA and DHEAS decline with age. It has been proposed that restoring the circulating levels of these steroids to those found in young people may have anti-ageing effects and improve wellbeing and sexual function. However this is not supported by the published literature. We have reviewed the physiology of DHEA and DHEAS in women and the published literature pertaining to the use of DHEA therapy for libido and wellbeing in postmenopausal women. The literature was searched using Medline (Ovid) and Pub-Med for original studies. Overall, the interpretation of data from randomised controlled trials conducted in well women is limited by inadequate sample size and short treatment durations with inconsistent results for the outcomes of libido and wellbeing. Studies of DHEA in women with adrenal insufficiency, although indicating potential improvements in mood and libido, are also limited by their short treatment phase durations. In addition safety data for DHEA therapy are lacking. The potential value of DHEA therapy for women still requires exploration in adequately powered well-designed randomised placebo-controlled trials. The studies of DHEA therapy in women with adrenal insufficiency suggest that this group is the most likely to derive health benefits from DHEA supplementation.

PMID: 17208951 [PubMed - as supplied by publisher]