“Of Mice and Men….”

“We need to treat individual women, not statistics” was the concluding sentence of an insightful BMJ Editorial 2019 [1]

However, as Caroline Criado Perez points out in her recent, science prizing-winning book, Invisible Women, in many instances there are no scientific or medical statistics on women[2].

Mouse
“Where are the females?”

The efficacy of drugs is predominately initially tested in vivo on male cells. So at inception, potentially many medications, which might have been effective in females are discarded at the earliest stage of research, because no effects are observed in male cells. The trend of the default male organism in research follows through into animal experimentation on male mice. Although animal models may not be entirely predictive of effects in humans, certainly the effects in female humans will be even less certain. Does it matter that research is conducted predominately on male tissue, male organisms and men? Thalidomide, specifically one of the optimal isomers, is a drug that had devastating teratogenic effects when taken by women. Indeed, a wide range of potential sex differences in the effects and metabolism of drugs has been reported. Furthermore the action of drugs, including adverse effects, can vary according the phases of the menstrual cycle, due to variations in circulating sex steroids. For example, certain drugs are likely cause arrhythmia in the follicular phase of the menstrual cycle[3]. Yet the effect of many drugs in females is not well understood, as research had not included females, let alone women in different phases of the menstrual cycle.

Why is research focused on males? There is an argument that the menstrual cycle in females is “too complicated” or including women in a study at difference phases of the menstrual cycle “will interfere with results”. Menstrual cycles have been around since women evolved, so this is not a phenomenon that is going to go away anytime soon. Therefore, welcoming the complexity of the intricate choreography of hormones during the menstrual cycle and during the lifetime of a women, is a more constructive approach. Certainly a more acceptable scientific approach is where the objective is to elucidate similarities and differences between men, rather than excluding the female half of the population and assuming no differences in physiology and metabolism exist. Furthermore there are differences between individual women. Individual women will be impacted by fluctuations of hormones during the menstrual cycle in different ways, depending on varying tissue sensitivities to steroids between individuals.

This concept is especially important in sports science where the vast majority of studies are conducted in males. As I outlined in my presentation recently at Barça Innovation Hub, before discussing external factors (training load, nutrition, recovery), researched in males, for female athletes is is vital to take into account internal bio-chronometers[4]. Circadian misalignment leads to suboptimal health and performance[5]. For female athletes, the most important cyclical variation of hormones during the menstrual cycle. Furthermore, these periodic changes in hormones have individual effects. Only when these are recognised can external factors be integrated with internal periodicity. In other words by taking account of individual internal variations, this makes it possible to provide personalised advice. Tracking menstrual cycles provides an important training metric as menstrual cycles are a barometer of healthy hormones[6]. As it becomes easier to track personal health and performance data on a daily basis, both researchers and individual women can gain a better understanding of how female physiology varies over the menstrual cycle. Optimising health and performance for the individual female athlete, makes for a stronger team.

What about in the clinical medical setting? I recently attended an excellent update on acute medicine for medical doctors. An eminent cardiologist presented a series of case studies, including a woman who started experiencing symptoms in the morning, which both she and doctors thought were due to indigestion. Eventually when this “indigestion” had not settled by later afternoon, she attended A&E. She had suffered an extensive myocardial infarction (heart attack). The cardiologist explained that even though she went to a hospital with an on-site primary percutaneous coronary intervention facility, unfortunately due to the long delay in presenting to hospital, the heart muscle had died. The opportunity had been missed to take her into the catheterisation laboratory to restore blood flow and function to the cardiac muscle. He outlined how this delay in diagnosis would have a big impact on her future quality of life and life span. Unfortunately this is not an isolated case. Women are far more likely to be misdiagnosed as not having acute coronary syndrome, when in fact they are indeed suffering a “heart attack”. Why is this? The “typical” presentation of myocardial infarction of central crushing chest pain with radiation to left neck and arm, disseminated to the public and medical students, is in fact only typical for men. Women present with “atypical” symptoms, in other words atypical for men[7]

Even where female specific statistics do exist, the emphasis should be on considering the individual woman in clinical context. The recent BMJ editorial on HRT emphasised providing women with high quality, unbiased information on which women can weigh up their personal risk/benefit outcomes from HRT. As, each woman can experience changes in hormones differently, including those occurring at the menopause; so the emphasis should be on an individual woman’s quality of life rather than epidemiological statistics[1].

There are important differences between mice, men and women.

References

[1] Rymer J, Brian, K, Regan L. HRT and breast cancer risk. BMJ Editorial 2019. dx.doi. org/10.1136/bmj.l5928

[2] Caroline Criado Perez. Royal Society Book Prize. Invisible Women. Publisher Chatto & Windus 2019

[3] Soldin O, Chung S, Mattison D. Sex Differences in Drug Disposition. Journal of Biomedicine and Biotechnology 2011, Article ID 187103 doi:10.1155/2011/187103

[4] N. Keay “Dietary periodisation for female football players” Barca Innovation Hub conference, Camp Nou, Barcelona, 9 October 2019

[5] N.Keay, Internal Biological Clocks and Sport Performance BJSM 2017

[6] N.Keay, What’s so good about Menstrual Cycles? BJSM 2019

[7] Khamis R, Ammari T, Mikhail G. Gender differences in coronary heart disease. Education in Heart. Acute coronary syndromes. BMJ Heart http://dx.doi.org/10.1136/heartjnl-2014-306463

 

 

 

Successful Ageing

As I am discovering, ageing is an inevitable process. However what can you do to keep as healthy as possible in order to get the most out of life?

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If you are a Masters athlete, you will know that moving into these age groups means it is advisable to change training emphasis in order to prevent injury and compete successfully. As discussed at the recent conference Royal Society of Medicine on Sports Injuries and Sports Orthopaedics, during the session on “The Ageing Athlete”, older athletes need a longer dynamic warm up with controlled mobilisation and muscle activation, together with strength and conditioning sessions to prevent injury. Moving into next age group every five years gives the opportunity to assess and modify training accordingly.

Childhood development has an impact on long term adult health. Essentially the most rapid changes and potential peaks attained during childhood and adolescence reflect optimal physical and cognitive functioning in later life. The evidence from population cohort studies was presented by Professor Diana Kuh, director of MRC Unit for Lifelong Health and Ageing, at the recent conference at the Royal Society of Medicine. Up to 66% of the decline in functional ability in ageing adults is related to childhood development. In the case of pubertal timing, Professor Kuh described that delay causes 20% reduction of volumetric trabecular bone accrual. In my 3 year longitudinal study of 87 pre and post pubertal girls, high levels of training delayed menarche and blunted attainment of peak bone mass (PBM). Conversely an optimal level of training did not delay menarche and improved bone mineral density compared to age marched sedentary controls. A similar long term effect is seen in older female athletes who have experienced amenorrhoea of more than 6 months duration. Even after retirement and resumption of menses pre-menopause, irreversible loss of bone mineral density (BMD) is seen. Professor Kuh argued for specific and personalised recommendations to individuals to support successful ageing.

From a personalised medical perspective, what about hormonal changes associated with ageing? Although in men testosterone levels decline with age, nevertheless the change is more dramatic in women at menopause where the ovaries stop producing oestrogen and progesterone. This results in increased risk after the menopause of osteoporosis, cardiovascular disease and stroke, together with other vasomotor symptoms and mood changes. With increased life expectancy comes an increasing number of women with menopausal symptoms and health issues which can negatively impact on quality of life. What about hormone replacement therapy (HRT)? HRT improves menopausal symptoms and reduces the risk of post menopausal long term health problems, provided HRT is started within ten years after the menopause. After this window of opportunity replacement oestrogen can actually accelerate cell damage. As with any medical treatment there will be those for whom HRT is contra-indicated. Otherwise the risk:benefit ratio for each individual has to be weighed up so that women can arrive at an informed decision. Regarding the risk of breast cancer, this is increased by 4 cases per 1,000 women aged 50-59 years on combined HRT. This compares to an additional 24 cases in women who have body mass index (BMI)>30 and are not on HRT. This underlines the important of lifestyle which is crucial in all areas of preventative medicine.

What type of HRT has the most favourable risk:benefit ratio? Oral preparations undergo first pass metabolism in the liver, so other routes of delivery such as transdermal may be preferred. There is also an argument that hormones with identical molecular structure are preferable to bio-similar hormones. What functional effect could a slight difference in sex steroid structure have? For example no methyl group and a side chain with hydroxyl group (C-OH) rather than a carbonyl group (C=O)? That is the difference between oestradiol and  testosterone.

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Testosterone
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Oestradiol

In the case of hormones with identical molecular structure to those produced endogenously, there are no potential unwanted side effects or immunogenic issues as the molecule is identical to that produced by the body. Although the oestradiol component in most HRT preparations in the UK has an identical molecular structure to endogenous oestradiol, there is only one licensed micronised progesterone preparation that is has an identical molecular structure. Synthetic, bio-similar progestins have additional glucocorticoid and androgenic effects compared to molecular identical progesterone which exerts a mild anti-mineralocorticoid (diuretic) effect.

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Progesterone
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Norethisterone (synthetic progestin)

With an increasing ageing population and increase in life expectancy, it is important to support successful ageing and quality of life with a personalised and specific approach.

For further discussion on Endocrine and Metabolic aspects of SEM come to the BASEM annual conference 22/3/18: Health, Hormones and Human Performance

References

Conference Royal Society of Medicine 17/1/17 “Sports Injuries and Sports Orthopaedics” Session on “The Ageing Athlete”

Optimal health: especially young athletes! Part 3 Consequences of Relative Energy Deficiency in sports Dr N. Keay, British Association Sport and Exercise Medicine

From population based norms to personalised medicine: Health, Fitness, Sports Performance Dr N. Keay, British Journal of Sport Medicine 22/2/17

Optimal health: including female athletes! Part 1 Bones Dr N. Keay, British Journal of Sports Medicine

Bio-identical hormone replacement therapy course. Marion Gluck Training Academy 27/1/17

The British Menopause Society

Royal College of Obstetricians and Gynaecologists