Research has long indicated that androgens, testosterone in particular, are linked not only with libido but with aggressiveness, particularly in the male. Animal research has been much more consistent in suggesting this hypothesis than human research has. However, the fact that sexual awakening in the adolescent is associated with rises in testosterone level, does link it to libidinal urges and possibly to aggression.

The testosterone levels of violent men have been measured time and again, and often, but not always, found to be higher than those in a control population. Violent sex offenders have been found, again not consistently, to have the highest testosterone levels of all. The effect of alcohol and drugs is variable; habitual use suppresses testosterone but occasional use can stimulate secretion, possibly as a feed-back effect of disinhibition.

This raises a further possibility that violent men are not violent because they have more testosterone to cope with, but that they have more testosterone because they are more violent. Traditional patterns of male activity might have developed because they stimulate the secretion of testosterone. If a woman can have an estrogen ‘high’, it seems likely that a man can have a testosterone ‘high’.

The main finding — that QOL was not significantly improved — was to be expected in this population. Symptomatic women were discouraged from participation, and vasomotor symptoms were reported by only 12% of the participants. Furthermore, it is unlikely that many women who had bothersome menopausal symptoms would volunteer for a study in which they had a 50% chance of receiving placebo for a prolonged time. Symptom relief is the most relevant factor for improvement of QOL with hormone therapy; therefore, women without symptoms are not likely to experience large improvements in their QOL. Nevertheless, even this older population showed improvements in sleep, physical functioning, and pain. Thus, it is possible that there was an effect on the QOL, but that the study was not designed to capture this information.

The more important question of effect on QOL in symptomatic women was addressed by a subgroup analysis of 574 women ages 50 to 54 years who reported moderate to severe vasomotor symptoms at baseline. Women in the estrogen and progestin group demonstrated a significant improvement of vasomotor symptoms (p < 0.001) and sleep quality (p=0.02), as compared to placebo. Despite this, improvement in QOL was not observed. This contradicts previous well-designed prospective trials.2 There are several limitations in this study’s design that may explain the failure of this analysis to detect an improvement in QOL. First, the primary objectives of the WHI did not include evaluation of the effect on QOL. The study, and particularly the subgroup, may not have had the power to detect a meaningful effect.

Second, the main instrument used to evaluate QOL was the RAND-36.1 Although a good measure of health-related functioning, it was not designed to assess variables relevant to QOL in postmenopausal women.3 For example, important domains, such as sexual function, are not addressed. The authors attempted to evaluate this variable by asking a single question with a four-point response scale: very unsatisfied, a little unsatisfied, somewhat satisfied, and very satisfied. This approach is clearly inadequate as a method for assessing change in such a complex aspect of human function. Nevertheless, the data in this subgroup revealed an improvement in the estrogen and progestin group that had borderline statistical significance (p=0.06). Thus, the RAND-36 was not designed to assess the “sense of well-being,” particularly in the postmenopausal population. Validated instruments such as the Utian Quality of Life Scale (UQOL) are available for this purpose, and should be utilized in future studies.3

Another weakness of this study was the high rate of drop-ins. Many women randomized to placebo initiated hormones. Symptomatic women were most likely to do this, which may have introduced bias toward the null hypothesis, thereby decreasing the likelihood of detecting an improvement in QOL.

In summary, it is incorrect to conclude, on the basis of this study, that estrogen plus progestin therapy does not improve QOL in women with vasomotor symptoms. Previous randomized controlled trials have provided evidence to the contrary. Furthermore, even in asymptomatic women this conclusion is questionable, as the study was not designed to evaluate QOL in postmenopausal women.

Additionally, observational studies reported by DiSaia, O’Meara, and Peters have supported this same conclusion. O’Meara assembled data from 2,755 women ages 35 to 74 years who were diagnosed with incident invasive breast cancer while they were enrolled in a large health maintenance organization from 1977 to 1994. Pharmacy data identified 174 users of hormone replacement therapy (HRT) after diagnosis. Each HRT user was matched to four randomly selected non-users of HRT with similar age, disease stage, and year of diagnosis. The rate of breast cancer recurrence was 17 per 1,000 person-years in women who used HRT after diagnosis and 30 per 1,000 person-years in non-users (adjusted relative risk for users, compared with non-users was equivalent to 0.50; 95% confidence interval was 0.30-0.85). Total mortality rates were 16 per 1,000 person-years in the HRT users and 30 per 1,000 person-years in the non-users.

DiSaia et al reported on 125 women who were breast cancer survivors with and without positive nodes, both ER positive and ER negative, who elected to take ERT or HRT. These patients were matched to 362 control patients from the same population base with the approximate ratio of four controls to one patient taking ERT or HRT. The risk of death was lower among the HRT survivors; odds ratio 0.28 (95% Cl 0.11-0.71). This analysis also did not suggest an adverse outcome with HRT use.

Peters interviewed 607 breast cancer survivors concerning ERT usage. Sixty-four patients indicated they had received some form of ERT after their breast cancer diagnosis. Eight patients were excluded because they had used only vaginal cream ERT. The remaining 56 received ERT as conjugated estrogens, an estradiol patch, or birth control pills. The median follow-up from diagnosis was 12.8 years and the median time on ERT since diagnosis was 6.4 years. One local recurrence and one contralateral breast cancer occurred during the follow-up period at 13.5 and 9.6 years respectively. There were no breast cancer deaths. The author also concluded that the use of ERT in a cohort of breast cancer survivors with tumors of generally good prognosis was not associated with increased breast cancer events compared with non-ERT users, even after a long follow-up period.

The question then remains as to whether all patients who have had breast cancer should be denied the benefits of estrogen replacement therapy. This is particularly relevant in the patient who has serious quality of life issues before her. At present, therapy with ERT/HRT is indicated in the management of quality of life issues, using lowest possible dose of hormone for shortest duration of time possible. Is it appropriate to deny a woman the option of taking replacement therapy for relief of her symptoms when there is no clinical evidence that it adversely affects outcome?

The benefits of estrogen therapy in the prevention of osteoporotic fractures were most recently confirmed in the largest clinical trial to date, the Women’s Health Initiative (WHI) (Cauley et al 2003, 1729-38). This study clearly demonstrates that therapy with continuous combined hormone therapy (0.625 mg conjugated equine estrogen + 2.5 mg medroxyprogesterone acetate ([CEE/MPA]) significantly decreases the risk of osteoporosis-related hip fractures and all other osteoporosis-related fractures in postmenopausal women. Despite these results, the authors concluded

“When considering the effects of hormone therapy on other important disease outcomes in a global index there was no benefit, even in women considered to be at high risk of fracture.” This conclusion is based on an analysis of stratification of fracture risk against the global index.

The statistics report the hazard ratio (HR) for the global index was not statistically significant for women in the lowest third (HR 1.20; 95% confidence interval [CI] 0.93-1.58) and upper third (HR 1.03 (95% CI 0.88-1.24) of the fracture risk scale (see below). The hazard ratio was statistically significant only for those patients in the middle third of the fracture risk scale (HR 1.23; 95% CI 1.04-1.46). The full text of the article states: “The interaction between treatment effect and summary fracture risk on the global index was not significant (p=0.54).Thus, there was no evidence of a net benefit, even in women at highest risk of fracture.” I readily admit to not understanding this sophisticated analysis but I believe that the data could equally well be reported that there was no evidence of net harm in those women at highest risk of fracture.

The global index was incorporated into the WHI as an overall measure of estrogen + progestin’s benefit vs. risk, which the investigators believe to be more significant than the evaluation of mortality alone. To my knowledge this innovative approach has not been used in other clinical trials, and has not been validated in any model. The WHI fracture risk scale is based on a validated model published by Black et al, which identified 20 different risk factors associated with fracture (Black 2001, 519-528). The differences between the WHI fracture risk assessment model and that described by Black et al are not trivial (e.g., the WHI did not include measurements of the hip bone mineral density for all patients, and did not assess peak adult height just to mention two items). The WHI fracture risk assessment model, like the global index, has not been validated. Thus, the conclusions based on the current WHI study are the result of an analysis of two nonvalidated models.

The global index, once validated, may indeed be an appropriate approach to look at overall benefits and risks of CEE/MPA. It becomes less appropriate when looking at individual outcomes. For example, there is abundant documentation of the devastation resulting from hip fracture including excess mortality in the first year, long-term morbidity and nursing home placement for those who survive the first year, the impact on the family of the affected patient, and the overall cost to the health care system. How can these serious complications be given equal weight to pulmonary embolism, which fortunately is fatal in only a small proportion of cases and is not associated with the long-term morbidity and health care costs that approach those of hip fracture? It is possible to perform a quality of life or cost analyses of each of the adverse outcomes included in the global index and take a very different approach to a benefit-risk analysis.

The above concerns notwithstanding, the WHI investigators have missed an important opportunity to add to our knowledge base. Epidemiologic studies have indicated that those patients who are at greatest risk for breast cancer are the least likely to develop osteoporosis and vice versa. None of the several articles documenting this (including at least two by one of the coauthors of this WHI paper) is cited in this manuscript! There appears to be little doubt that the skeleton is an estrogen-dependent tissue, as is the breast. It is not surprising that those at lowest risk for fracture (possibly determined by higher lifetime estrogen exposure) are also at greatest risk for breast cancer (by the same mechanism). What we should have learned from the WHI investigators is whether this relationship is true in their study population as well. 8102 women were assigned to placebo, and one-third of these were assigned to the low-fracture risk group. We are told that their annualized incidence of fractures was 1.3%, half the incidence seen in women assigned to the high-fracture risk group (2.7%). What was the breast cancer incidence in these groups in the placebo arm? There certainly was as much or more data available in this study than in any of the previous reports relating osteoporosis protection and increased breast cancer risk. If breast cancer did not contribute to the HR of the global index, then which adverse outcomes were noted in those on HT? We cannot ascertain that important question from this WHI manuscript.

Finally, there is a crucial element missing from the WHI, particularly as it relates to the skeleton. The most rapid postmenopausal bone loss occurs during the first 5 years, slowing down substantially thereafter. The WHI population included only 16% to 17% of women who were within 5 years postmenopause (there was no need to include these patients because the benefits of estrogen in the early menopause have been repeatedly demonstrated in numerous controlled clinical trials). Women using estrogen for management of the menopause do not need other medications for skeletal protection. This beneficial effect only lasts as long as the patient continues estrogen therapy; bone density and fracture risk are back at baseline within 1 year of discontinuing the hormone.

In clinical practice, we have known for decades that women tend to take a holiday from estrogen whenever a prescription runs out and do not refill the prescription if her menopausal symptoms do not recur. This long predates WHI and should not change post-WHI. Most women did not and do not take estrogen for as long as five years postmenopause. However, there has always been a substantial minority of women who do not tolerate this estrogen-free period, and quickly experience a recurrence of symptoms leading to the reinstitution of estrogen therapy.

In conclusion, I believe the following statements can be made:

* Estrogen + progestin is now the only osteoporosis therapy documented to decrease fracture occurrence even in women not specifically selected as being at increased risk of fracture.

* The benefits of estrogen in controlling the symptoms of menopause are not questioned as a result of the WHI study findings.

* Patients will be receiving skeletal protection as long as they use estrogen +/- progestin for control of menopausal symptoms.

* Other effective therapies that can protect the postmenopausal patient from fracture are available once she no longer experiences symptoms of menopause.

Recent media accounts of the findings from the HT trials of the Women’s Health Initiative (WHI) have increased women’s concerns about using hormones for relief from menopausal symptoms and have heightened the need for clinicians to take a more individualized approach to counseling their menopausal patients.

CME program, Scientific Update on Hormones and Postmenopausal Health, is designed to assist clinicians in providing their patients with accurate information and individualized counseling about menopausal health issues and HT. This slide series allows physicians to earn a maximum of 1 category 1 credit per presentation toward the American Medical Association’s Physician’s Recognition Award (AMA-PRA) through the University of Wisconsin Medical School.

This large cohort study1 confirms the findings from the Women’s Health Initiative (WHI) (2,3) that current users of estrogen plus progestogen (EPT) are at an increased risk of invasive breast cancer (RR 2.0). This study also confirms prior observational studies4 that estrogen therapy alone (ET) increases the risk of breast cancer (RR1.30).

Over one million women (1,084,110) ages 50 to 64 years (average age 55.9 years) who were initially cancer-free were followed from 1996 to 2001 in a national screening program. Mean follow-up was 2.6 years for breast cancer incidence and 4.1 years for mortality. Primary endpoints of the study were diagnosis of breast cancer and deaths from breast cancer. Overall, current use of ET/EPT (Estrogen therapy/Estrogen and Progesterone therapy) was associated with a statistically significant increased risk of breast cancer incidence (RR 1.66; 95% CI 1.58-1.75) and breast cancer mortality (RR 1.22; 95% CI 1.00-1.48) compared to nonusers. Past use did not increase the risk of incidence or mortality and the risk of breast cancer decreased with time since last use. Current users of estrogen plus progestogen were at the highest increased risk (RR 2.0; 95% CI 1.88-2.12) of invasive breast cancer, compared to current ET users (RR1.30; 95%CI 1.21-1.40). In current users of each type of HRT, the risk of breast cancer increased with duration of HRT use. This risk appeared to be linear over time and was less in heavier women. In women with a BMI > 25, the relative risk of breast cancer for all users of HRT was 1.46 versus 1.97 for those with a BMI < 25. Of note, vaginal or other local EPT formulations did not increase the risk (RR 0.67; 95% CI 0.30-1.49). No significant differences in risk were found between specific types or doses or regimens of systemic ET or EPT. However, breast cancer risk increased as duration of use increased.

Although this study is observational, the results are very similar to those of the WHI and the results predicted by the Collaborative Group on Hormonal Factors in Breast Cancer Study4, which lends credence to these findings. Prior observational studies have suggested that ET alone increases the risk of breast cancer (RR 1.3). Ten years of HRT with ET alone is estimated to result in five (95% CI 3-7) additional breast cancers per 1000 women, and EPT combination to result in 19 (95% CI 15-23) additional cancers per 1000 women.

Evaluating a broader range of hormone therapy products than the WHI (which examined just one specific type of estrogen and progestogen, conjugated equine estrogen plus medroxyprogesterone acetate), the Million Women Study found very little variation between specific estrogen and progestogen products, their doses, their routes of administration, or whether the regimen was continuous or sequential. For estrogen-only users, increased risk was seen with oral, transdermal, or implanted formulations. No increased risk was seen with vaginal or local estrogen preparations. Progestogen only preparations were associated with an increased risk, but based on only nine incident breast cancers. Tibolone was also found to increase breast cancer risk, but less than combined EPT.

On an absolute basis, the breast cancer risk from ET is not very high. Many physicians are awaiting the results of the estrogen alone arm of the WHI to determine if estrogens in the absence of a progestin also increase the risk of breast cancer. However, a calculation of expected breast cancer incidence rates in the ongoing WHI ET arm estimates that there would be 70 new breast cancer cases in the women taking placebo and 78 in those taking estrogen alone. Thus, the WHI trial may not have sufficient statistical power (i.e., enough women in the study) to detect the slightly increased relative risk seen in the Million Women Study.

In this study, the follow-up was 2.6 years for cancer incidence and 4.1 for mortality. The increased risk in breast cancer became apparent within 1 to 2 years of starting treatment, irrespective of type of hormone therapy used. Once hormone therapy was stopped, the risk began to decline, and by 5 years reached the same level as never users. Increased mortality was seen, but it was of borderline statistical significance. Longer follow-up is needed from this study and the WHI to determine any effects on mortality from breast cancer.

Likewise, male-to-female transsexual women are sometimes prescribed drugs (anti-androgens) to decrease the level of testosterone in the body and allow for the effects of estrogen to develop. Women may also use testosterone therapies to treat or prevent loss of bone density, muscle mass and to treat certain kinds of depression and low energy state.

There are some interesting cases where testosterone level in the body can be increased:

No 1:
Experts recommend one of the safest ones and most importantly legal ones is to increase zinc mineral intake.Also brewers yeast, whole grains and wheat have high levels of zinc in them and they are totally natural.The minimal dose of zinc for men is 15 mg per day, but up to 50 mg daily can be taken, anything more than that can cause unwanted side effects and can be hazardous for your health.

No 2:
In a 2003 study, it show that serum testosterone levels reach a peak seven days after abstaining from ejaculation.

No. 3:
Recent research has suggested that alcohol consumption in women can temporarily raise testosterone levels. A 2006 BBC article states : “ According to medical research, testosterone – the hormone connected to male characteristics such as aggression and sex drives – rises in women by up to 50% when they are drunk. In men, its level drops down.”

They went back to natural estrogen, a cumbersome and expensive product, harvested from the urine of pregnant mares. The mares are fitted with a collection cup attached to a hose and confined in a narrow stall for the entire eleven months of their pregnancy. As soon as possible after the birth of their foals, who are routinely slaughtered, the mares are re-impregnated and the urine-collection process begins again.

If the pharmaceutical companies were to get women hooked the best time was at menopause when they were in estrogen withdrawal and begging for a fix. At least that was what the researchers thought that hot flushes, joint pains, sleeplessness, etc., added up to. The new mixtures were the methadone rather than the heroin. For some reason the women did not stay hooked. The selling and the product design were relaunched time and again. Sub-dermal implants seemed to lose their effectiveness; women required bigger closes, the implants became ineffective more quickly, menopausal symptoms recurred at shortening intervals. The manufacturers of sex steroid preparations, like the manufacturers of cigarettes, had what they wanted, addiction, and they were just as unwilling to talk about it. An underground network of pushers w-as set up; women, all users themselves, held HRT parties, bring-and-buy sales and coffee mornings, to spread awareness so that women would ask their doctors to prescribe.

Women who take estrogen definitely tend to look younger than their years. Their skin remains smoother, moister, oilier and more flexible – in other words younger. That doesn’t mean you should take estrogen for cosmetic purposes alone. Younger-looking skin is just one of the magical consequences of HRT that researchers have been unable to substantiate; as far as laboratory investigations can establish, exogenous estrogen has no effect on the epidermis or supporting structures.

Once a large-scale trial has been set up it has its own momentum. A positive correlation of smoking with incidence of Alzheimer’s has recently been observed. As for estrogen, it is said to have an effect on human cognitive function. But the only evidence is from short-term administration of estrogen to small mammals in the laboratory, animals not normally noted for intricacy of brain function.

Sex steroids can hardly be expected to be neutral in their effect on behavior, mood, cognitive function and so forth, especially if we consider that the pharmacologic versions of sex steroids are administered at much higher levels than those occurring naturally. We are also beginning to realize that there are reciprocal interactions between steroids and behavior. In other words, as hormones influence behavior, so behavior influences hormones. The more expert the endocrinologist, the more respect she/he has for the synergistic interactions of body chemicals; unfortunately most health practitioners have only an elementary understanding of endocrinology and are far too ready to believe in quick-fix remedies for perceived malfunction.

What is claimed for Alzheimer’s is also claimed for cancers, except those of the endometrium and breast, which are considered estrogen-dependent. The data are difficult to interpret. Women on replacement estrogen are three times as likely to develop endometrial cancer as women who are not, but opposing the estrogen with progestogens is thought to control the risk factor. British doctors believe that after stopping HRT women should continue to take progestogens for two years but American doctors have yet to be convinced of the usefulness of opposing estrogen at all. Women on HRT have twice the rate of breast cancer after nine years, and women on combined regimes are four times as likely to have breast cancer after six years. HRT used to be denied to women who have had a brush with the disease, but now HRT users may also take tamoxifen if the risk of breast cancer is considered significant. The constant crying up of HRT has the effect of making women who are denied the therapy feel hard done by, when the truth is that most women who could use replacement estrogen don’t. The latest cross-national study of HRT users in Europe calculated current users as only one-third of women actually going through menopause and no more than 13 per cent of post-menopausal women. About a quarter of post-menopausal women reported use at some time.

Still fortunes are to be made and professional clout to be accumulated by setting up large-scale cohort trials to track the incidence of the diseases of ageing in a post-menopausal population that faithfully persists in dosing itself with estrogen. The difficulty will be to find that population, because if current trends persist women will use HRT during the period of menopausal discomfort as a symptomatic treatment and then abandon it. The drug houses, who anticipated easy pickings as women remained on their product for the term of their unnatural lives, are perplexed. They want explanations of this poor compliance. They blame voices like my own crying in the wilderness, effortlessly overcoming the booming sound of their endless promotion of their product in the medical press, and the equally energetic distribution of free samples to GPs. The truth is that selling estrogen as a panacea was a miscalculation. Nobody knows better than women that biology offers no free lunches. In women with wombs and ovaries estrogen has got to be opposed by progestogens if uterine hyperplasia is not to result. This results in administration regimes that are onerous, especially when the adverse effects of exogenous progestogens, bloating, headaches, mood swings, etc., are taken into account. Then there is the question of monthly bleeding. Every year the drug houses present new methods of administration, tacitly admitting that they have not got the mixture right. There will be no definitive large-scale cohort trial of the prophylactic effects of post-menopausal estrogen because there are insufficient examples of long-term use of any single method.

Adult females make it themselves out of cholesterol converted by their gonads and their adrenal cortex first into progesterone, then into testosterone and then into estrogen. The ovaries carry on producing estrogen long after ovulation has ceased, more than twelve years in fact. The adrenal glands atop the kidneys produce estrone to boost it; all steroid hormones are lipophilic, that is, soluble in fats and easily diffused through membranes. They bind with intracellular receptor proteins and the resultant complex binds to DNA. The scale of effects of this process is as yet hardly glimpsed. What we know and are prepared to say is that ‘estrogen lifts our moods and gives us a feeling of well-being’. It probably does that by influencing some of the neuropeptide transmitters in the brain that regulate how we feel and think, probably oxytocin and vasopressin, together with the enkephalins and dynorphins, opioids produced in the brain.

Oxytocin is particularly interesting not only because it can be shown to have specific functions connected with arousal and orgasm in both males and females, but because neurons containing oxytocin receptors have been found in regions of the brain that suggest a role in bonding behavior. Such data might give the impression that personality is a simple bio-chemical cocktail and can be changed just by upping some part of the mixture. In fact the cocktail has some 4,000 elements that are continually being shaken and stirred; the overall and ultimate effects of adding a jigger of something new are unknowable.

The sex hormones estrogen and progesterone are closely related to anabolic steroids and, like them, affect mood and behavior. People suffering disruptions of their normal biochemical balance will report personality disturbances. The behavioral effects of added estrogen are difficult to quantify; estrogen will not increase libido, for example, as it exerts little action on the clitoris, but it does increase receptivity in that it controls the vaginal environment.

We know enough to know that sex steroids are powerful and that they have complex interactions with other substances, which would seem to be good reason not to introduce similar substances that would replicate or exaggerate or annihilate any part of the wonderfully intricate sequence. In the case of recreational drugs reasonable people are only too ready to accept the idea that interference is foolhardy; when it comes to exogenous estrogen, which is a drug like any other, we are suddenly undisturbed by the prospect of lifelong dependency. Estrogen is now being tried and found effective as a mood-altering substance; it has been used successfully as a symptomatic treatment for severe post-natal depression.