Testosterone replacement reduced elevated levels of inflammatory cyto-kines in a group of men with CHD and symptomatic androgen deficiency in a randomized, placebo-controlled trial. This dialing-down of the systemic inflammatory state may have salutary stabilizing effects on atherosclerotic plaques, explained Dr. Malkin of Royal Hallamshire Hospital, Sheffield, England.

These observations, if confirmed in larger studies incorporating clinical event end points, could have broad implications. The prevalence of hypogonadism is known to be elevated in men with CHD; in one representative study, the rate was 23%.

Dr. Malkin reported on 20 men with CHD and androgen deficiency symptoms who were randomized to 1 month of testosterone replacement or placebo, then crossed over to the other arm for a second month. Baseline mean total testosterone in study participants was 6.7 nmol/L; the lower limit of normal is 8.3 nmol/L.

Of the inflammatory cytokines measured in the study, the greatest impact of testosterone replacement was on tumor necrosis factor (TNF)-[alpha]. Mean TNF-[alpha] decreased by 4.1 pg/mL during replacement therapy, compared with a 1.5 pg/mL increase during the placebo phase.

Interleukin (IL)-1[beta] levels decreased by 0.17 pg/mL during testosterone replacement, a significant improvement over the mean 0.3 pg/mL gain while patients were on placebo.

IL-10, an anti-inflammatory cytokine, increased by 0.32 pg/mL during testosterone therapy and decreased by 0.87 pg/mL during the placebo phase, a difference that bordered on statistical significance.

Total serum cholesterol declined by 0.26 mmol/L in the testosterone phase, compared with a 0.005 mmol/L reduction while on placebo, a nonsignificant trend.

This pilot study is the first ever to evaluate the effect of testosterone replacement on inflammatory and anti-inflammatory cytokines in men with CHD, according to Dr. Malkin. The hormonal therapy has previously been shown to inhibit atherosclerosis in castrated male animals fed a high-cholesterol diet.

When 100 mg/day of the phosphodiesterase type 5 (PDE5) inhibitor sildenafil failed to improve erectile dysfunction symptoms, patients were randomized to add daily applications of a topical testosterone gel or a placebo gel. Among 67 men who completed 4 weeks of treatment, the testosterone group had improvements in erectile response, orgasmic function, and overall patient satisfaction, compared with the placebo group, said Dr. Shabsigh of Columbia University, New York, and also director of the New York Center for Human Sexuality.

Trends toward greater efficacy in the testosterone group after 8 and 12 weeks were not statistically significant.

Dr. Shabsigh has been a consultant, advisor, investigator, meeting participant, and lecturer for the companies that make sildenafil and the testosterone gel used in the study (AndroGel) — Pfizer Inc. and Solvay Pharmaceuticals Inc., respectively.

“It is important to screen men who present with erectile dysfunction for the presence of hypogonadism, especially populations at risk such as aging men, men with type 2 diabetes, men with the metabolic syndrome, and specifically men who fail PDE5 inhibitor therapy alone,” he said. “Testosterone may be considered for the treatment of erectile dysfunction in men with low to low-normal testosterone who fail PDE5 inhibitor therapy alone.”

Patients in the study had a mean age of 59 years, similar to the mean ages in most medical trials of PDE5 inhibitors for erectile dysfunction. They conducted the trial after clinical observations and animal studies suggested a synergistic effect when various forms of testosterone were used with various PDE5 inhibitors.

Lorraine Dennerstein, A.O., M.B.B.S., Ph.D.m D.P.M.
Ofice for Gender and Health, Department of Psychiatry, The University of Melbourne, Melbourne, BIC 3010, Australia.

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.

http://www.liebertonline.com/doi/abs/10.1089/jwh.2006.15.898

The 75 women, aged 31-56, were studied at nine clinical centers throughout the United States. All had undergone surgery 1-10 years previously, before natural menopause occurred. All were taking conjugated equine estrogens, had low levels of serum and serum free testosterone, and reported markedly impaired sexual function.

Among the 65 women who completed the study, free and biolavailable levels of testosterone rose to the normal and high-normal range with the testosterone patch, but not with the placebo patch.

Concomitantly, the mean score and index of sexual functioning rose from 52 at baseline to 81 on testosterone therapy. Scores for frequency of sexual activity and sexual pleasure also rose significantly. During active treatment, the women also reported having more sexual fantasies and masturbating more often than when they used the placebo patch and before they entered the study.

The subjects’ scores on measures of general well-being improved. Feelings of vitality increased while those of depression and anxiety decreased, the researchers reported (N. Engl. J. Med. 343 [10]: 682-88, 2000).

The treatment was well tolerated, with four women withdrawing because of adverse effects: Two women became anxious or agitated, one had a recurrence of a nipple discharge, and the fourth woman had an application-site skin reaction to the placebo patch.

Measures of hirsutism and acne did not change. Similarly, the treatment did not “negate the beneficial effects of oral estrogen-replacement therapy on hot flashes and serum concentration of high-density lipoprotein cholesterol,” Dr. Shifren and associated noted.

It is now been clearly demonstrated both in cross-sectional and longitudinal studies that testosterone levels decrease over the lifespan in males. Because of the increase in sex hormone binding globulin in aging, the decline in testosterone levels is even greater when a measurement of free of bioavailable testosterone (free testosterone together with that weakly bound to albumin) is made. It has been estimated that 5% of men aged 40 years and 70% of men aged 70 years have bioavailable testosterone levels below the normal value of young men; in other words, they are hypogondal. This translates into 20 million to 25 million men in the United States who have undergone the equivalent of the male menopause

Because the decline in testosterone levels is gradual – approximately 10% per decade after the age of 40 years – it has drawn less attention that the dramatic change that occurs in females at the time of the menopause. In addition, female menopause occurs because of failure of the ovaries, leading to an increase lutenizing hormone (LH) to accompany the fall in estrogens, whereas the male menopause is predominantly due to a failure of the hypothalamic-pituary unit (i.e., secondary hypogonadism) and thus is not associated with an increase in LH. Thus diagnostic difficulties, such as a need for a more sophisticated (can’t understand the word) and the failure for an increase in LH, have obscured the clear development of a male equivalent of the female menopause.

The male menopause is often referred to as the andropause, or androgen deficiency in aging males (ADAM), or viropause (when coupled with the onset of erectile dysfunction). The acceptance of male menopause has had a checkered past, with the first recognition occurring in ancient Roman times and later in the early Chinese medical literature. It was first scientifically explored toward the end of the 19^th century, when Charles Edouard Brown-Sequard, then in his 70s, injected himself with a testicular extract to enhance his function. This led to the era of rejuvenation by testicular extract injections followed by chimpanzee testicle transplants, which were pioneered by Serge Voronoff. With the isolation and manufacture of testosterone in the 1940s, a number of studies appeared suggesting that testosterone may alleviate the symptoms of the male climacteric.

It has not been until the past decade, however, that the publication of a number of controlled studies has led to the scientific validation that some of the symptoms of male menopause can be alleviated by testosterone replacement. A cross-sectional study found a strong correlation between free androgen index and the decline in appendicular muscle mass and muscle strength in older persons. Subsequent testosterone replacement studies have shown that in older hypogondal men testosterone increases muscle mass and upper limb strength. It is well recognized that aging is associated with a decline in muscle mass and strength. This melting away of muscle with aging has been termed sarcopenia, and it appears that it is in part due to age-associated testosterone deficiency.

Testosterone deficiency also has been shown to by associated with a decline in function in the aging male. Recently, it has been shown that testosterone administration improves function when administered to older males undergoing rehabilitation. Testosterone decline has been clearly associated with the decrease in libido that occurs at middle age and beyond in older males; testosterone replacement reverses this problem. In addition, testosterone is necessary for the elaboration of nitric oxide plays an important role in vasodilation necessary for penile erection, and lack of testosterone results in relatively soft erection.

Numerous other positive effects of testosterone now have been demonstrated in the older male. These include an increase in bone mineral density, which should lead to a decrease in hip fractures. Although hip fractures occur lately in males than in females, they are associated with a greater mortality rate. In older males, the fat hormone leptin increases in the circulation, and the levels of leptin are decreased by testosterone. This increase in leptin levels has been associated with the physiological anorexia of aging and the subsequent weight loss that occurs in older men.

Hematocrit levels fall with aging these levels are restored to normal by testosterone. There is decline in cognitive ability with aging that is strongly associated with the decline in bioavailable testosterone. Testosterone replacement improves age-related cognitive decline, and in an animal model of Alzheimer’s disease testosterone replacement reversed the memory defects. Low testosterone levels are associated with coronary artery disease, and testosterone replacement improves myocardinal function.

At this stage, the existence of a series of symptoms associated with the age-associated fall in testosterone levels can no longer be argued. In addition, these symptoms are reversed by testosterone replacements. Thus, the existence of the male menopause, or ADAM, is incontrovertible. The availability in the United States of new forms of testosterone gel, now make it unconscionable for the physician not to screen and to treat hypogondism in older males.

“We have all seen visible evidence that the United States is currently facing an obesity crisis, said Bethany Klopfenstein, M.D., a fellow in the division for endocrinology of the OHSU School of Medicine. The obesity epidemic in not only expanding the waistlines of Americans. It is also being connected to the unhealthy surge in type 2 diabetes cases, cardiovascular disease and other associated disorder. For women, a sudden increase in weight often occurs following menopause. This not only raised obesity-related health concerns. The weight gain also can be an emotionally difficult occurrence for aging women.”

To conduct this research project, scientists observed a group of 46 pre-and postmenopausal women. In the postmenopausal group, some of the women involved in the study were receiving hormone replacement therapy, others were not. By analyzing data from study participants, researchers determined that the drop in estrogen levels commonly associated with menopause is linked to an increase in a form of the hormone cortical.

Another key finding was that postmenopausal women who were not receiving hormone replacement therapy had higher cortisol levels than those who were receiving therapy. On average, these untreated women with higher cortisol levels also witnessed an oncrease in abdominal fat when compared with women receiving the therapy.

“These findings also suggest that estrogen replacement therapy protects women from developing high cortisol levels and increased abdominal fat,” said Jonathan Purnell, M.D., an associate professor of medicine (endocrinology, diabetes and clinical nutrition) in the OHSU School of Medicine and a researcher in OHSU’s Center for Study of Weight Regulation and Associated Disorders. “We believe that by preventing this raise in cortisol, we can possibly delay or prevent weight issues and the many weight-associated disorders in some of these women.”

To future confirm the relationship between estrogen replacement and cortisol levels, researchers treated seven postmenopausal women not already undergoing hormone replacement therapy woth a synthetic form of estrogen. After one month of therapy, these women, who all previously had heightened cortisol levels, witnessed decreased cortisol at levels close to that of premenopausal women.

The findings also suggest that over time, this group of women a may also witness a decrease in abdominal fat. However, more long-term studies involving delayed estrogen replacement therapy would be required to confirm this theory.

The link between obesity and disease of aging has been confirmed in studies using calorically limited to approximately 65% of their ad labium caloric intake, the mass of tat tissue is markedly decreased and the animals live as much as 50% longer than animals fed ad labium. Furthermore, the onset of neoplastic and cardiovascular disease in these animals is significantly delayed. It has not yet been established whether the benefits of caloric restriction are mediated by the decreased secretion of cyokined by fat cells.

In one of our studies, we looked at the effect of surgical removal of visceral fat on carbohydrate metabolism. We removed visceral fat from one group of rats and performed abdominal surgery without removing visceral fat in another group of sham-operated control rats. Although the visceral fat removed for each rat made up only 10% of their total body fat content, the rats that had visceral fat removed showed decreased insulin resistance and improved insulin action that was not observed in the sham-operated control rats. In addition, we showed that the removal of visceral fat also decreased the expression of TNF-α by subcutaneous fat cells.

These experiments provide powerful evidence that visceral fat tissue has a direct effect on age-associated insulin resistance in rats. Now the challenge is to identify the specific hormonal and/or metabolic signals produced by visceral fat cells that lead to diabetes and cardiovascular diseases. It is likely that the expression of some fat tissue-derived cytokines, such as TNF-α or leptin, mediate these effects, it is tantalizing to speculate that reducing the levels of these cytokines night not only decrease insulin resistance but might also decrease the risk if diabetes and cardiovascular disease.

Learn more at REVITA Anti-Aging Center

Since 1946, the UK Medical Research Council has collected medical, psychological, and demographic date on more than 5000 people on everything for verbal and nonverbal reasoning to algebra and visual memory. Tapping in this data base, psychologist Marcus Richards of University College London and his colleagues found that the smarter women is during childhood, the more likely she will begin menopause later in life. After adjusting for factors such as education, number of children, and socioeconomic states, they found that higher cognitive scores correlated with later menopause.

The finding, reported in the 22 July issue of Neurology, suggests that the link between hormones and brain development might be stronger than researchers suspected, pushing the connection and back to an earlier age. Other research has shown that hormones including estranger can influence both brain development and reproductive aging.

Education, knowledge and advances in reproductive techniques are rapidly growing.

From Biomedicine: January 2000, Vol.3 No1