Monthly Archives: February 2012

UPDATE FEB 2012: WANNABE ALTERNATIVE HRT eg TIBOLONE LIVIFEM IS INFERIOR TO APPROPRIATE HORMONE REPLACEMENT.

24 Feb 2012  Sharifah Zainab asks about safety of tibolone after more than 10 years on it; and whether and how to wean off it.
 
No new singnificant studies change the hard evidence that tibolone may
do more harm (than good) eg may increase stroke, breast cancer, fatness and vaginal bleeding. The comprehensive Cochrane review of last week affirms this:          Cochrane Database Syst Rev. 2012 Feb 15;2:CD008536.Short and long term effects of tibolone in postmenopausal women. Formoso G ea WHO Collaborating Centre ,  Modena, Italy.  “Tibolone is an option available for the treatment of menopausal symptoms, based on short-term data on its efficacy. However, there is a need to consider the balance between the benefits and risks of tibolone as there are concerns about breast and endometrial cancer as well as stroke.   MAIN RESULTS: When compared to placebo, tibolone was more effective in relieving the frequency of vasomotor symptoms (two RCTs, n = 847; OR 0.42), although only the 2.5 mg/day dose of tibolone was significantly better than placebo; but with increased vaginal bleeding (seven RCTs, n = 7462; OR 2.75). When compared to equipotent doses of combined HT, tibolone reduced vaginal bleeding (15 RCTs, n = 6342; OR 0.32) but was less effective in relieving the frequency of vasomotor symptoms (two RCTs, n = 545; OR 4.16).As for long term safety, two major RCTs of tibolone versus placebo provided the most relevant data. An RCT of 3098 women with breast cancer and menopausal symptoms was halted after 3.1 years because of increased tumour recurrence (OR 1.50). However, in another RCT that selected osteoporotic women with negative mammograms (n = 4506) tibolone was associated with a reduction in breast cancer compared to placebo after 2.8 years (OR 0.32) although the trial was not specifically designed to assess that outcome and the number of overall events was low. In the same RCT, an excess risk of stroke was observed (OR 2.18). There was no clear evidence of a tibolone effect on endometrial cancer compared with placebo given the low number of events (seven RCTs, n = 8152; OR 1.98).There was no evidence of a difference in long term safety between tibolone and combined HT. AUTHORS’ CONCLUSIONS: Tibolone, used at the daily dose of 2.5 mg, may be less effective than combined HT in alleviating menopausal symptoms although it reduced the incidence of vaginal bleeding. There was evidence that treatment with combined HT was more effective in managing menopausal symptoms than was tibolone. Available data on the long term safety of tibolone is concerning given the increase in the risk of breast cancer in women who had already suffered from breast cancer in the past and in a separate trial the increase in the risk of stroke in women whose mean age was over 60 years. Similar concerns may exist for estroprogestins but their overall benefit-risk profile is better known and is more directly related to women with menopausal symptoms.”

Why use a risky synthetic  drug designed for profit when as this column repeatedly stresses, there are so many safe natural supplements that reduce all risks?

update : Jan 2010:  WEIGHT GAIN ON TIBOLONE:

Hester asks about a better option HRT since she has gained 5kg in a few months on Livifem tibolone.

One cannot treat an unseen patient by email based on a one-line history.

all one can advise is,  read about the serious risks and deficiencies of quick-fix heavily marketed snakepills compared to finely tuned natural products eg human hormones and other natural supplements evolved/designed over millennia rather than recently in for-profit laboratories.

There are  two  new  illuminating papers on tibolone since the November review:

Dr Peter Kenemans writes from the Netherlands Vrije Universiteit:  Tibolone revisited: ‘still a good treatment option for healthy, early postmenopausal women‘.

Drs de Melo and Pompei from Sao Paolo UniversityTibolone reduces osteoporotic fracture risk and breast cancer risk, but increases the risk of stroke.

The Ziaei paper detailed below  addressed only weight issues, and describes average results.

In the  Royal Free Hospital  study in London in 1995, they found that  in their 300-patient experience over 8 years ie medium term –  an impressive 2400 patient years- that  “The major side effect was weight gain and/or a tendency to bloating and oedema which occurred in 11.28% of our women”.

This doesnt mean that tibolone increases fatness- most women inexorably get fatter and frailer once past menopause. Certainly they dont do this if they maintain good balance of human hormones- testosterone, estradiol, progesterone, thyroid and insulin-  with a sensible blend of  all the other other scores of useful  supplements, and  diet and exercise.

By contrast, shortterm controlled trials – 6 months from Turkey (2006, and 2009) and  Ziaei’s 9month trial- show that in the short term, tibolone reduced body fat and waist.

BEAR IN MIND THAT MANY STUDIES SHOW THAT EVEN JUST 10 YEARS OF APPROPRIATE SEXHORMONE THERAPY FROM EARLY IN MENOPAUSE HAS MAJOR LONGTERM BENEFITS ON REDUCING ALL RISKS eg FRACTURE, CARDIOVASCULAR AND DEMENTIA RISKS IN LATER LIFE – without any significant adverse effects. . There do not appear to be published any studies of tibolone or any other wannabe substitute  over  a mean of more than 5 years. But women now often survive more than one-third of  their lifespan post menopause- that is another 35+ years. No modern designer chronic drug  has been used and observed reasonably continuously to be safe for much more than 10years .  The only designer drugs which have been used continuously for much longer are perhaps the old diuretics and some  antihypertensives.

Tibolone is yet another designer progestin- and the Women’s Health Initiative showed that, even when started appropriately soon after menopause,  progestin (medroxyprogesterone MPA)  reversed the myriad benefits of  premarin alone  in respect of worsening fracture, breast and cardiovascular risks.

This contrasts with natural supplements like eg minerals and vitamins, the plant extracts reserpine and the  prohormone metformin,  and all the human hormones- thyroid, insulin, cortisone, testosterone, estradiol- which many patients have used continuously for over 40 years with nothing but benefits in appropriate doses.

So as always its up to  you the patient to decide whose advice, what to try. All any doctor can do is (in a brief consultation) offer advice from his experience and ongoing update studies – which may not be up to the minute. You have to decide about shortterm benefits versus long-term possible risks. In the few months on tibolone, are you just swollen-eg  needing to reduce salt?- or fatter  waist with higher bodyfat,  bloodpressure, insulin resistance etc?

Nov 18, 2009
a new study last month bears out the futility of spin,  focussing only on benefits in abstracts. The small short (9month) trial by Ziaei ea in Tehran Iran  on Comparative effects of continuous combined hormone therapy and tibolone on body composition in postmenopausal women concludes  that The effect of tibolone on body composition is favorable and therefore tibolone may be regarded as an alternative to continuous combined postmenopausal hormone therapy MHT .  Tibolone significantly increased weight, BMI and FFM and decreased WHR after the treatment in comparison with baseline (p < 0.05). However, only weight and BMI increased significantly in the CEE/MPA group after the treatment (p < 0.05). There were significant increases in weight, BMI and fat mass in the control group after 9 months..  So they confirmed what has been obvious all along: that postmenopausal women gain weight and fat post menopause, and on xenohormones (premarin+provera) gain even more fat at the expense of losing lean mass. A synthetic xenohormone progestin like tibolone increases weight, BMI,  and FFM (it’s androgenic property) –   but they ignored the multiple deficiencies of tibolone (unlike appropriate HRT), that it increases breast cancer,    stroke, vaginal bleeding and endometrial cancer and perhaps CVD, and fails to reduce either all-cause or breast cancer mortality, or depression or  dementia. .

SUMMARY: No published trials have yet shown any alternatives as good as appropriate HRT (ie estrogen -progesterone- testosterone) for overall long term benefits post menopause.
eg  with  the synthetic progestin tibolone – the 3 year LIFT trial had to be stopped early due to strokes, and in  the 3year LIBERATE trial breast cancer recurrence increased 44%. As the International Menopause Society IMS keeps stressing, all synthetic sex hormones are inferior to appropriate balanced sex hormone replacement for eg menopause symptom relief, and against osteoporosis fractures. Many different modalities relieve the short-term menopause symptoms, but these matter far less than the long term preventable degenerative effects of hormone deficiency- which are the primary concern of patients, carers, internists and geriatricians. The average gynecologist (surgeon) deals only with  menopause symptoms, which mostly subside well within 10 years ie by age 60years – but that’s when all aging medical not gynecological problems start,   increasing  incapacity problems – vascular, cancer, fracturing, mental, mood, fattening, frailty, sex, incontinence and thus loss of decades of quality life.

Analysis To August 18, 2008 ·

The LIFT trial report by Steve Cummings et al (NEJM   August 14, 2008  The Effects of Tibolone in over 4000 Older Postmenopausal Women -mean 68years)  is another nail in the coffin of tibolone.

The LIFT trial was stopped after a median of just 34 months because Tibolone doubled strokes – up from 0.34% to 0.66% per year. .

Tibolone,  unlike appropriate HRT, has no significant reported benefit on all-cause mortality, on cardiovascular disease (which increased by 37% – p0.28), on memory/ dementia and on depression , although  it almost halved fractures –  but  it doubled the risk of stroke, trebled rate of breast discomfort and vaginal bleeding- which  rose from 2.9% to 9.5%; even the incidence of cervical dysplasia rose from 3.2% to 7.6%. And it increased weight in this already overweight cohort by an excess of 0.6kg in 3years..

Breast and colon cancer rates were too low to draw conclusions about benefit. “The tibolonegroup also had a decreased risk of invasive breast cancer (relativehazard, 0.32; 95% CI, 0.13 to 0.80; P=0.02) and colon cancer(relative hazard, 0.31; 95% CI, 0.10 to 0.96; P=0.04)” – but the incidence of these and coronary artery disease were each only 2 – 3% pa on placebo..

So it finally  confirms tibolone as just another synthetic progestin looking for a disease to treat, much inferior to real supplements including  appropriate HRT (vitamin D and   lowdose parenteral human estradiol-testosterone-progesterone) for reduction of all the major diseases of aging. There are no contraindications to, only benefits from  such long term appropriate  steroid hormone replacement.

Update November 2009:

In a further LIFT trial report (Ettinger & Cummings Sept 2008), Tibolone treatment for 3 years minimally increased endometrial thickness, hyperplastic polyps, and endometrial carcinoma.

In a Danish trial , tibolone had no benefit on cartilage degeneration. whereas appropriate HRT has benefit (Forsblad Scandanavia 2004).

In the massive 31-country 2002-4 LIBERATE trial (Feb 2009 Kenemans ea ) in over 3000 women after breast cancer, recurrent breast cancer increased 44% with tibolone over a mean of 3.1yrs. Tibolone was not different from placebo with regard to other safety outcomes, such as mortality (respectively 72  vs 63 patients), cardiovascular events (14 vs 10), or gynaecological cancers (10 vs 10).

A report in September 2009 from Health and Human Services’ Agency for Healthcare Research and Quality suggests that tamoxifen, raloxifene, and tibolone used to treat breast cancer significantly reduce invasive breast cancer in midlife and older women, but also increase the risk of adverse side effects.

Regretfully, tibolone has not fulfilled early  hope that it might be the first designer drug since metformin to be another panacea, reduce all-cause morbidity and mortality even in postmenopausal  women.

It appears that despite 40years  use elsewhere, tibolone (not invented and marketed by a US corporate)  has still not been  and is unlikely to be licensed for use in USA – like SERMS (tamoxifen, raloxifene) its benefits are so limited that they are not  enough to balance it’s risks. .. doubling the risk of stroke and increasing the already high  general risk of breast cancer by 44% in only 3 years. Whereas  all (ie multisystem) risks and frailty are reversed by the safe threescore mix of natural supplements plus appropriate balanced physiological human hormone replacement as regularly set out in this column. .