Rest of Volume 1, Issue 4

The rest of issue 4 consists of:

A review of a book called Mitochondrial DNA Mutations In Aging, Disease And Cancer, mostly positive.

Three article reviews:

• Aging health risks and cumulative disability, by Vita AJ, Terry RB, Hubert HB, and Fries JF. Gives evidence in support of the compression of morbidity hypothesis, showing lower disability rates for people with lower health risks in the 8 years to the 75 year mark, but similar life expectancy at age 85 if they get there.
• Telomerase and the Aging Cell: Implications for Human Health, by Fossel M. Review of experiments upregulating telomerase in-vitro.
• Fantastic Voyage in the San Francisco Magazine, by Berger K. About Geron.

The usual other sections: web watch, literature watch and calendar.

Risks of Testosterone Treatment in Elderly Men

Summary: The risks of testosterone supplementation aren't a big deal either.

Interestingness: 1

Paper by Peter J Snyder, MD in the Journal of Anti-Aging Medicine, Volume 1, Issue 4, Winter 1998.

(((This paper is a subset of the previous paper, focusing on risks.)))

Higher testosterone concentration seems to be related to higher probability of having prostate cancer. In one study, testosterone measurements for about 22000 men were taken and those men were tracked for the following ten years. 222 of those men that developed prostate cancer were age matched with 444 non-prostate cancer men. Men with the highest quartile of testosterone concentration were twice as likely to have developed cancer as those in the lowest quartile. Those with the highest quartile of sex hormone binding globulin (SHBG) which binds testosterone were half as likely to have developed as those in the lowest quartile.

Prostate cancer is testosterone dependent (((not shown))). Autopsies of 249 men showed 41% of those in their 50s and 63% of those in their 60s had occult (((unknown))) prostate cancer (((hardcore numbers))).

Prostate size also seems to be dependent on dihydrotestosterone, which is created from testosterone by 5alpha reductase. Blocking of 5alpha reductase with finasteride reduced prostate size, increased maximal urinary flow rate and decreased symptoms of benign prostatic hyperplasia (BPH) (((enlarged prostate))) compared to placebo.

Testosterone probably lowers high density lipoprotein (HDL) concentrations. In one study, inhibiting testosterone release with an antagonist of gonadotropin-releasing hormone (GnRH) raised HDL, but blocking testosterone release and injecting testosterone simultaneously didn't.

Testosterone replacement in hypogonadal men also increased apnea episodes and increased concentration of haemoglobin in small studies.

(((Summary: Testosterone wasn't good to begin with)))


Abstract follows:

As men age, serum testosterone concentrations fall, and they experience decreases in energy, bone mineral density, and muscle strength, which at least in part may be due to the fall in testosterone. Consequently, testosterone treatment has been considered for aging men. The possible benefits of testosterone treatment of aging men should be balanced, however, by its possible deleterious effects, including an increase in the prevalence of prostate cancer, benign prostatic hyperplasia, sleep apnea, lipid abnormalities, erythrocytosis, and hypercoagulability, all of which to some degree are testosterone dependent.

Androgens in Aging Men: Do Men Benefit from Testosterone Replacement?

Summary: Shit-all good comes from testosterone supplementation in old men.

Interestingness: 1

Paper by Carrie J Bagatell, MD and William J Bremner, MD, PhD in the Journal of Anti-Aging Medicine, Volume 1, Issue 4, Winter 1998.

(((This paper is the male equivalent of the previous two posts. Testosterone supplementation is much less used than estrogen and thus much less is known about it. This paper is short on numbers and graphs, so not much to report)))

Total and free testosterone levels decline during aging in men. Young men with low gonad activity (((and therefore low testosterone levels))) show lower muscle mass and higher fat content than men with normal activity. Supplementing with androgens in those men increases muscle mass, decreases fat content, increases libido and frequency of erections and ejaculation (((don't know if enough to put them back to standard levels))). This increase in sexual function does not work with older men though (((that seems to be the summary of the whole paper: it works for hypogonodal young men, it doesn't work for old men))), and most older men with erectile dysfunction do not have low levels of testosterone. Use of gonadotropin-releasing hormone analogs (GnRH) triggers a similar condition to having low gonad activity (((makes no sense to me with that name))). When this is done in older men (((prostate cancer??))), it triggers lower bone density.

In a very small study, long term use of testosterone increased libido (((partially contradicting the previous paragraph))). It did not help cognition in a different study. Improvement in hand grip strength was noted in many studies. No benefit in bone density or good bone markers were noted on older men under androgen supplementation.

Risks also don't appear to be a big deal: decreases in high-density lipoprotein (HDL) in young men and some worries about it contributing to the growth of prostate cancers exist. In older men, hematocrit and hemoglobin fraction increase a lot, with 25% of test cases developing polycythemia (((disease of the blood where too high a fraction of the volume of blood is made up of red blood cells))).

The authors think that selective androgen receptor modulators would be useful, and some are being studied in primate models (((but I fail to see the benefits))).

(((There's too few benefits shown by testosterone to pay much attention to it)))

Abstract follows:

Most cross-sectional studies and one recent longitudinal study suggest that testosterone levels in healthy men decline slowly and that this decline begins during middle age. The decline in "free" or unbound testosterone is greater than the decline in total testosterone levels. Physiologic sequellae of lower testosterone levels may include a decrease in muscle mass, increase in body fat, decreased bone density, and a variety of changes in sexual function. Long-term studies of androgen replacement are currently in progress. Short-term studies suggest that, for some men, androgen replacement may increase libido and muscle strength and decrease abdominal fat. The available data suggest that androgens do not generally worsen symptoms of prostatic hypertrophy or stimulate the development of prostate cancer. Lipid profiles may be slightly improved during androgen replacement, but the long-term effects of androgens on the cardiovascular system are unknown. Hematocrit and hemoglobin frequently rise in response to androgen administration. In most men, these increases are small, but in some men they can be significant. Liver toxicity can occur with use of alkylated androgens, but it is extremely rare with the use of testosterone esters. Men receiving androgens should have periodic monitoring of their prostate, serum prostate-specific antigen level, lipids, hematocrit, and liver functions. Future androgens, with minimal effects on the prostate, may become available for clinical use.

Hormones and Breast Cancer

Summary: Estrogen replacement hormones cause breast cancer

Interestingness: 2

Paper by Graham A Colditz, MD, Dr.Ph, FAFPHM in the Journal of Anti-Aging Medicine, Volume 1, Issue 4, Winter 1998.

(((This paper is a subset of the previous one, with a few more details. This summary is going to be very short)))

Higher levels of estrogens in postmenopausal women are associated with higher incidence of breast cancer and lower breast cancer survival. In a smallish study, 130 women, risk of breast cancer was 3.2 (1.4-7.0) times higher among postmenopausal women in the highest quartile of estrogen levels compared with those in the lowest. Other studies give similar results. Yet other studies suggest that risk of breast cancer is associated linearly with accumulated cell divisions in breast epithelial cells.

Since women with the lowest levels of postmenopausal estrogen are more likely to get hormone replacement therapy (HRT), the effect of HRT on breast cancer will be partially hidden if not correcting for this factor. Also, because lower age of menopause is associated with a much lower risk of breast cancer, women on HRT have a lower risk of breast cancer than non-users of the same age (((that only makes sense to me if the non-user hasn't undergone menopause, or is it that the effect of later menopause enough to override total accumulated effect of HRT of all practical time spans?))). A large meta-analysis, of a total of 50000 breast cancer cases and 100000 non-breast cancer cases, estimates risk of breast cancer increases 2.3% (1.1-3.6) per year on HRT. Most studies in the meta-analysis were only using estrogens (((but other parts of the paper claim that progestins wouldn't help and might worsen the risk))). From the meta-analysis, they estimated that for every 1000 postmenopausal women who start HRT at 50, six more will get breast cancer if they use it for ten years, and 12 more if they use it for 15.

(((Summary: again, not particularly influential in life expectancy. Also, I think I remember some big study that came up in the last couple of years, maybe 2008, that most likely supercedes anything in the last couple of posts. This is the main reason I gave both these papers a low interestingness rating. The CHD benefits, if I remember correctly, turned out not to be real)))


Abstract follows:

The role of estrogen replacement therapy in the cause of breast cancer continues to be debated. This article reviews the literature on hormones and breast cancer, including articles on cell proliferation, endogenous hormone levels, epidemiologic studies, and the risk of breast cancer. A cause of cancer is defined as a factor that increases the probability that cancer will develop in an individual. A causal relationship between female hormones and breast cancer is consistently suggested by several lines of argument, especially the relationship between duration of use and risk of breast cancer, dose-response with endogenous hormone levels, and biologic plausibility. The magnitude of the increase in risk of breast cancer caused by using hormone replacement is comparable to that seen in delayed menopause. The positive correlation between endogenous hormone levels and risk of breast cancer supports a causal relationship between exogenous hormone use and breast cancer. The increase in risk of breast cancer with increasing duration of use, which does not vary substantially across studies, offers further evidence for a causal relationship. The reduction in mortality rate with short-term use of hormones, although strongest among women with risk factors for cardiovascular disease, adds complexity to the risk-to-benefit trade-off associated with long-term hormone use. All evidence supports a causal relationship between both endogenous estrogens and the use of estrogens and progestins, and breast cancer incidence in postmenopausal women. Hormones act to promote the late stages of carcinogenesis among postmenopausal women and to facilitate proliferation of malignant cells. Strategies for relief of menopausal symptoms and long-term prevention of osteoporosis and heart disease that do not cause breast cancer are urgently needed.

Estrogen Therapy For Menopause

Summary: Review of health benefits and risks of estrogen on post-menopausal women

Interestingness: 2

Paper by Kathryn A Martin MD in the Journal of Anti-Aging Medicine, Volume 1, Issue 4, Winter 1998.

(((This paper is a dense but nicely written review of the effects of estrogen on post-menopausal women. It is hard to summarise since it already is a summary. I'm going to pick out interesting snippets)))

The postmenopausal ovary produces almost no estrogen. Estrogen in postmenopausal women is mainly produced by conversion of androstendedione (((don't know where that happens))). Average age of menopause is 51 (((or was back then, and probably in the USA. Last third of their life spent with assumedly little estrogen, although there is no plot or numbers of levels of estrogen in the paper))).

Some problems associated with this drop in estrogen are vaginal dryness, pain during sex and symptoms similar to urinary tract infection. Hot flushes are also experienced by 75% of women which commonly leads to insomnia and its derivative problems. Osteoporosis is also common, and the risk of coronary heart disease (CHD) goes up by a lot (((doesn't say))). Estrogen in hormone replacement therapy (HRT) helps with the flushes, and the vaginal and urinary tract problems. It also stops the osteoporosis and decreases the risk of CHD (((by 50% it seems from later in the paper))) when given in doses equivalent to 625 micrograms in conjugated form, or equivalent. Although a 15-year study on postmenopausal women did not notice any difference between estrogen and non-estrogen users with respect to cognitive function, a meta-analysis of epidemiological and control studies claims the risk of dementia for estrogen users to be 0.71 (0.53-0.96) compared to non-users (((but the paper abstract discourages that conclusion))).

Five types of HRT are used:

• estrogen only (625 micrograms conjugated)
• cyclic combined: estrogen (625 micrograms conjugated) for days 1-25 of the month, medroxy-progesterone acetate (MPA, a progestin), 5mg, days 13-25. This is the most popular option.
• continuous combined: estrogen (625 micrograms conjugated), and MPA (2.5 mg) without breaks.
• other estrogen preparations: Different variants all equivalent to the 625 micrograms of conjugated estrogen. Some as vaginal creams.
• low dose contraceptives: these are mostly used by women around menopause time

Risks of HRT when supplying only estrogen include increased risks of gallstones, endometrial hyperplasia and cancer (((uterus))), and breast cancer. The increase in uterine cancer can be cancelled by adding in progestin, but it doesn't seem to help with the breast cancer. Breast cancer risk is a factor of 1.35 (1.21-1.49) compared to baseline after 5 years of HRT.

Estrogen raises high density lipoprotein (HDL) and decreases low-density lipoprotein (LDL), but progestin has the opposite effect (((although it later says that women under the combined therapy had HDL levels similar to women only taking estrogen, and that the protective effects against CHD were similar in both groups))). Estrogen suppresses platelet function and is a potent vasodilator. It also improved 10-year survival of women with narrowing of their coronary arteries. On a different study though, HRT did not improve survival of women with CHD and risk of events (((heart attacks?))) was higher during the first year compared to placebo.

Some new substances can act as estrogen agonists in some tissue and estrogen antagonists in others. Raloxifene, for example, appeared, in one study, to have an estrogen agonist effect with respect to osteoporosis and lipid profile, but antagonist with respect to breast and endometrial tissue. Even though it affected lipids in a positive way, it did not show improvement with respect to artherosclerosis.

(((Summary: I don't think it'd have a major effect on longevity)))

Abstract follows:

The medical management of menopause continues to be a topic of controversy. Although many of the benefits of estrogen therapy have been well established (treatment of estrogendeficiency symptoms, prevention of osteoporosis, and prevention of coronary heart disease), the potential risks of breast cancer are of great concern. Although many postmenopausal women are candidates for hormone replacement therapy (HRT), many choose not to take it because of fear of breast cancer or concerns about potential side effects and continued menstrual bleeding. Therefore, making choices about potential therapies after menopause can be a difficult one for both women and their health care providers. An important principle of HRT is the notion of short-term versus long-term use, as the goals of both therapy and riskbenefit profiles are different. Although most perimenopausal and postmenopausal women are candidates for short-term HRT (with the exception of those with a history of breast cancer), no general consensus is found regarding who should or should not receive long-term HRT. Other new areas of clinical investigation in the field of menopause and HRT include the possible impact of estrogen on cognitive function, the role of exogenous androgen replacement for libido, and the role of a new class of drugs known as "selective estrogen receptor modulators" (SERMs). Given this rapidly changing field, it is likely that the medical management of menopause will continue to evolve in the coming years.