# Exercise as it relates to Disease/Effects of HRT and high-impact exercise on skeletal muscle in post-menopausal women

This is an appraisal of the research article by Sipilä, S., Taaffe, D.R., Cheng, S., Puolakka, J., Toivanen, J. and Suominen, H. (2001). Effects of hormone replacement therapy and high-impact physical exercise on skeletal muscle in post-menopausal women: a randomized placebo-controlled study. Clinical Science (London)101(2):147–157.

## What is the background to this research?

Decline in functional capacity and strength due to loss of muscle mass as women age is linked to higher risk of falls leading to injury and early death. As this decline coincides with the menopause, it begs the question of whether female sex hormones have a role, either alone or with other logical agents such as exercise, in regulating muscle performance.
This research was the first double-blind placebo-controlled study to investigate the separate and combined effects of Hormone Replacement Therapy (HRT) and high-impact exercise on skeletal muscle in post-menopausal women. Prior to 2001, research in the field was limited to:
* Several experimental studies on the effects of exercise showing beneficial outcomes for strength and, in the case of high-impact exercise, for bone mineral density;
* A few experimental studies on the effects of HRT on muscle mass and performance with varied results; and
* One study on the effects of HRT and weight bearing exercise showing that exercise alone increased fat-free mass and strength in 60 – 72 years old women, but there was no added effects when combined with HRT.

## Where is the research from?

At the time of this research, Sipilä, Taaffe, Cheng and Suominen held positions with the University of Jyväskylä, Finland. Puloakka and Toivanen held positions with the Central Hospital Jyväskylä, Finland.
Current positions and background of the academic researchers are as follows:
* Sipilä is a Professor in Exercise Gerontology at the University of Jyväskylä, Finland. http://www.gerec.fi/henkilosto/henkilot/CVSipil.pdf
* Taaffe is Professor in Exercise Gerontology, Edith Cowan University, Western Australia. http://www.ecu.edu.au/schools/medical-and-health-sciences/our-staff/profiles/professors/professor-dennis-taaffe
* Suominen is Professor Emeritus in Exercise Gerontology, University of Jyväskylä, Finland. https://www.puijosymposium.org/@Bin/171442/suominen.pdf
* Cheng is a Professor in Sport and Health Sciences, University of Jyväskylä, Finland. http://www.oulu.fi/sites/default/files/Oulu_Cheng.pdf
All the research participants were living in the city of Jyväskylä, Finland. Finland currently ranks 23 out of 188 on the Human Development Index.http://hdr.undp.org/en/countries/profiles/FIN

## What kind of research was this?

This was a randomized double-blind placebo-controlled study which is widely considered the gold standard in intervention based studies. This kind of study seeks to eliminate the influence of variables which may lead to a bias or incorrect estimate of the treatment effect.
* The participants were randomized via a lottery for allocation to one of the four groups.
* The HRT was administered in double-blind format to ensure the researchers were unaware of which women received either active hormones or placebo until the follow-up measurements were performed.

## What did the research involve?
##### Participant Characteristics

The study was made up of women aged 50 – 57 from the city of Jyväskylä, Finland. They had:
* Their last menstruation at least 6 months previous and not more than 5 years ago;
* No serious medical conditions;
* No current or previous use of medications including oestrogen, fluoride, calcitonin, biophosphonates or steroids (unless taken more than 2 years ago and for no longer than 6 months);
* Follicle-stimulating hormone levels greater than 30 i.u./litre; and
* No contra-indications for exercise and HRT.

##### Number of Participants and Group Types

| Measurement Points | Exercise Only (Ex) | HRT only (HRT) | Exercise and HRT (ExHRT) | Control Group (Co) |
| At 6 months | 15 | 17 | 13 | 17 |
| At 12 months | 12 | 15 | 10 | 15 |

##### Interventions

* The EX and ExHRT groups undertook 12 months of progressive physical training through two supervised and four home sessions per week. The exercise sessions included circuit training (with skipping, jumping, hopping and leaping activities), high impact aerobic dancing, resistance training and core work.
* The HRT and Co groups were instructed to continue with their usual routine and to keep a diary of their physical activity.
* The HRT and ExHRT groups were given combined oestradiol (2 mg) and noretisterone acetate (1mg) continuously via tablet for 12 months.

##### Measurement Methods

* Height and body mass (using bioelectrical impedance).
* Muscle performance via knee extensions (for isometric muscle force) and vertical jumps (for explosive-type muscle performance).
* Cross-Sectional Analysis (CSA) of the thigh and lower leg lean muscle tissue (using CT scans and needle muscle biopsies).

##### Considerations

* From the 6 to 12 months measurement times there were either 2 or 3 participants who dropped out or were excluded from each group. This was due to either a lack of time or interest, health concerns, or non-compliance with HRT or exercise protocols.
* The women in the ExHRT group participated in the supervised sessions 20% more often than the Ex group women (but no significant difference was observed for the home sessions).

## What were the basic results?

In a nutshell:
* Separately, both HRT and exercise showed improvements for explosive muscle performance, but only exercise showed some improvement for muscle force.
* Combining exercise and HRT showed significant higher improvements for both explosive muscle performance and muscle force when compared with the separate results.
* HRT showed notably more improvement than exercise alone for both muscle mass and muscle composition. The positive HRT effect was further augmented when combined with exercise.
More specifically:
The study resulted in increases in the vertical jump height test in all groups except the control group at 12 months: ExHRT 17.2%; HRT 6.6%; Ex 6%; and Co -7.2%.
The knee extension torque test saw an improvement for the ExHRT group of 8.3%. After some improvement from the base line for the HRT and Ex group at the 6 months mark, there was a subsequent decline at the 12 months assessment mark, leaving the Ex group only slightly improved from their baseline, and the HRT group under their base line. The Co group had a decline at both assessment points.
The lean tissue CSA of the quadriceps was increased significantly in the ExHRT (7.1%) and HRT (6.3%) groups when compared with the Ex (2.2%) and Co (0.7%). The lower leg lean tissue CSA was also significantly increased in the Ex HRT (9.1%) the HRT (6.6%) groups when compared with the Ex (3.0%) and Co (4.1%) groups.
The lean body mass and body fat measurements showed positive changes for all groups except the control group as can be seen in the following table:
| Lean Body Mass (kg) | Exercise Only (Ex) | HRT only (HRT) | Exercise and HRT (ExHRT) | Control Group (Co) |
| Baseline | 45.9 | 45.8 | 45.7 | 47.4 |
| 12 months | 46.9 | 46.9 | 46.8 | 47.1 |
| Body Fat (%) | Exercise Only (Ex) | HRT only (HRT) | Exercise and HRT (ExHRT) | Control Group (Co) |
| Baseline | 31.2 | 33.9 | 28.3 | 29.7 |
| 12 months | 30.3 | 32.2 | 26.9 | 29.8 |

## What conclusions can we take from this research?

This research demonstrates HRT positively influences skeletal muscle mass and performance. It also confirms what we know about high impact exercise having a positive effect on skeletal muscle. Of particular noteworthiness was the exponential effect resulting from combining HRT with exercise.
The researchers claim the most interesting result for them was the independent effect of HRT on muscle mass and performance. These results built on previous evidence demonstrating the anabolic effect of oestrogen and also its androgenic and bone sparing effects when combined with progestin.
Furthermore, when considering the similar research that has been conducted since this study was undertaken, we can see there is a growing body of evidence that HRT influences the skeletal muscle environment. A meta analysis of 23 studies from 1987 to 2007 (including the Sipilä et al. research) concluded that, overall, HRT alone could result in approximately 5% greater strength in post-menopausal women. Also, a 2011 reviewof relevant human and animal studies cited findings that point to an enhanced pro-anabolic muscle environment when women are exposed to HRT by specifically studying the level of muscle damage from high intensity resistance exercise.
As such, this research stands the test of time and provides us with good evidence for the influence of HRT on skeletal muscle performance when used independently, and shows how HRT creates an even more powerful intervention when combined with high impact exercise. This allows the post-menopausal woman to optimise her approach to maintaining her muscle integrity as she ages.

## Practical advice

This research demonstrates the case for post-menopausal women to consider HRT as a suitable intervention for positive muscle performance outcomes. However, it should be noted the scope of this appraisal was limited to exploring the effects of HRT and exercise on skeletal muscle alone. It did not consider how the effects of HRT, positive or negative, impact women in other ways. Therefore, noting the variability that can occur based on personal characteristics and methods of hormone therapy administration, the use of HRT by peri and post-menopausal women should only be considered on an individual basis, and with knowledge of the associated risks, under the guidance of an experienced medical practitioner.
Irrespective of HRT administration, this research provides further evidence of the positive effect of exercise, in this case high impact exercise, on muscle performance for ageing women and should be considered as a worthwhile intervention. As such, exercise prescriptions which include jumping, skipping and bounding activities at least three times per week would be of value.

## Further reading

Additional Review Articles
* Atapattu, P.M., Fernando, D., Wasalathanthri, S. and de Silva, A. (2015).Menopause and exercise: Linking pathophysiology to effects. Archives of Medicine. http://www.archivesofmedicine.com/medicine/menopause-and-exercise-linking-pathophysiology-to-effects.php?aid=7062
* Maltais, M.L., Desroches, J. and Dionne, I.J.(2009). Changes in muscle mass and strength after menopause. Journal of Musculoskeletal and Neuronal Interactions, 9(4):186-97. https://www.ncbi.nlm.nih.gov/pubmed/19949277
* Kendall, K.L. and Fairman, C.M., (2014). Women and exercise in aging. Journal of Sport and Health Science, 3(3):170-79. http://www.sciencedirect.com/science/article/pii/S2095254614000386
Useful Menopause Information
* Australasian Menopause Society, including information about finding a doctor in your state: https://www.menopause.org.au
* Benefits and risk of hormone therapy: http://www.menopause.org/for-women/menopauseflashes/menopause-symptoms-and-treatments/hormone-therapy-benefits-risks
* Menopause management: https://jeanhailes.org.au/health-a-z/menopause/menopause-management
* ASCM Exercise recommendations for menopause-aged women: http://www.acsm.org/public-information/articles/2016/10/07/exercise-recommendations-for-menopause-aged-women

## References

* ↑ Samson, M.M., Meeuwsen, I.B., Crowe, A., Dessens, J.A., Duursma, S.A. and Verhaar, H.J,. (2000). Relationships between physical performance measures, age, height and body weight in healthy adults. Age Ageing, 29(3):235–242.
* ↑ Sipilä, S., Taffe, D.R., Cheng, S., Puloakka, J., Toivanen, J. and Suominen, H. (2001). Effects of hormone replacement therapy and high impact physical exercise on skeletal muscle in post-menopausal women: a randomized control trial. Clinical Science, 101:147–57.
* ↑ Bothwell, L.E., Greene, J.A., Podolsky, S.H. and Jones, D.S. (2016) Assessing the Gold Standard-Lessons from the History of RCTs. The New England Journal of Medicine, 374:2175-2181.
* ↑ Misra, S. (2012). Randomized double blind placebo control studies, the “Gold Standard” in intervention based studies. Indian Journal of Sexually Transmitted Diseases and Aids, 33(2): 131–134.
* ↑ Rance, N.E. and Max, S. R. (1984). Modulation of the cytosolic androgen receptor in striated muscle by sex steroids. Endocrinology, 115, 862–866.
* ↑ Verhaar, H. J., Damen, C. A., Duursma, S. A. and Scheven, B. A. (1994). A comparison of the action of progestins and estrogen on the growth and differentiation of normal adult human osteoblast-like cells in vitro. Bone, 15, 307-311.
* ↑ Wood, A. J. J. (1994). Drug therapy; Hormonal treatment of postmenopausal women. New England Journal of Medicine, 330, 1062–1071.
* ↑ Michaëlsson,K., Baron,J.A., Farahmand,B.Y.et. al. (1998). Hormone replacement therapy and risk of hip fracture: population based case-control study. British Medical Journal 316, 1858–1863.
* ↑ Tiidus, P.M. (2009). Estrogen and HRT promote a proanabolic skeletal muscle environment in older women. Journal of Applied Physiology, 107: 1367-1358.
* ↑ Greising, S.M., Baltgalvis, K.A., Lowe, D.A. and Warren, G.L. (2009). Hormone Therapy and Skeletal Muscle Strength: A Meta-Analysis. The Journals of Gerontology, 64A, 1071–1081.
* ↑ Tiidus, P.M. (2011). Benefits of Estrogen Replacement for Skeletal Muscle Mass and Function in Post-Menopausal Females: Evidence from Human and Animal Studies. The Eurasian Journal of Medicine, 43(2), 109-114.
* ↑ Dieli-Conwright, C. M., Spektor, T.M., Rice J.C., Sattler, F.R. and Schroeder, E.T. (2009). Influence of hormone replacement therapy on eccentric exercise induced myogenic gene expression in postmenopausal women. Journal of Applied Physiology, 107, 1381–8.