# Exercise as it relates to Disease/Menstrual cycle disruptions in response to strenuous exercise training

This is a critique of the article titled "Evidence for a Causal Role of Low Energy Availability in the Induction of Menstrual Cycle Disturbances during Strenuous Exercise Training" by NANCY I. WILLIAMS*, DANA L. HELMREICH†, DAVID B. PARFITT†, ANNE CASTON-BALDERRAMA‡, AND JUDY L. CAMERON

## What is the background to this research?

Throughout recent decades, women have become increasingly physically active. Despite the extensive health benefits of exercise and physical activity, intensive, strenuous exercise can subject female athletes to an entirely unique set of risks. Reproductive disfunction includes:
* oligomenorrhea (infrequent menstrual periods fewer than 6-8 per year)
* amenorrhea (the cessation of menstrual periods)
* and luteal phase defects (reduced secretion of progesterone/no response from endometrium to normal stimulation of progesterone)
and can be developed as a result of the participation of female athletes in strenuous exercise training. The mechanisms behind exercise induced reproductive dysfunction have been studied over previous decades. These studies have examined physical and psychological stress of exercise, as well as low body weight or fat, as potential causal factors.
Despite these factors contributing to exercise induced reproductive dysfunction, an accumulation of evidence from a variety of studies conducted on both humans and animals, suggests that negative energy balance is the leading cause. Negative energy expenditure refers to energy expenditure exceeding energy intake, which can result in the secretion reproductive hormones being suppressed and infertility after extended lengths of undernutrition.
The article under review takes into consideration previous studies that simply suggests a correlation between negative energy balance and reproductive dysfunction as opposed to firm evidence about the causal relationship. Considering this, the article analyses exercise-induced amenorrhea in non-human primates while having complete control over dietary intake and exercise. Testing to confirm if reproductive dysfunction was developed as a result of increased energy expenditure from daily vigorous exercise or from a different factor of exercise by determining exercise induced amenorrhea was reversed by increasing energy intake while completing the same exercise schedule.

## Where is the research from?

Williams, Helmreich, Parfitt, Caston-Balderrama and Cameron conducted their research at the University of Pittsburgh, Pennsylvania and had their research published in The Journal of Clinical Endocrinology & Metabolism (JCEM).
The 8 cynomolgus monkeys used for the study were housed at the University of Pittsburgh Primate Research Laboratory.
Credibility here is maintained as editors at JCEM may not take part in the editorial management of any reports of their own research or or close relation to their own research

## What kind of research was this?

Nancy I Williams, Dana L. Hemlreich, David B. Parfitt, Anne Caston-Balderrama and Judy L. Cameron conducted a longitudinal study over a 7-24month time period to examine the development and reversal of exercise induced amenorrhea, focussing on the role of low energy availability.
Longitudinal studies generally follow a particular population or individual over an extended period of time, generating data that has no external influence. They are useful for determining relationships between risk factors and disease development and treatment outcomes over time.

## What did the research involve?

The research involved observing 8 non-human primates and their changes in reproductive hormones throughout the development of exercise induced amenorrhea. This was done by conducting two experiments. First, they tested energy utilisation during vigorous exercise resulted in reproductive hormone suppression by determining whether exercise induced amenorrhea was reversed by increasing energy intake. The second text examined the link between changes in the hormone T3 and reproductive function during the development and reversal of exercise induced amenorrhea.

### Animals

* Eight 2.10 kg - 3.45 kg adult female cynomolgus monkeys were used (housed at university of Pittsburgh Primate research Laboratory)
* Temperature in lab remained at 24 degrees +/- 2 degrees.
* All monkeys received the same daily meal of approximately 300kcal at 1600h each day.
* " All experiments were performed in compliance with the regulations of the animal care and use committee of the University of Pittsburgh "

### Blood Sampling Procedures

* Blood samples for LH, FSH, E2 and progesterone measurements were collected from the animals every other day, before exercise and feeding.
* Hematocrit was measured every 6wks and remained within normal range in all monkeys for the duration of the study.

### Monitoring Reproductive Function

* Prior to commencement of study, the monkeys were familiarised with daily checks for menses which consisted of swabbing the vaginal area.
* Before the study commenced, several normal menstrual cycles were documented.
* A monkey was determined to be amenorrheic if at least 3 menstrual cycles were missed with low levels of E2 and progesterone.

### Exercise Training

* Monkeys were trained on standard treadmills.
* When fully trained, they ran for 2hr/day, 7days/week with a 3 min break every 30 minutes.

### Experimental Designs

* Overfeeding face to reverse exercise induced amenorrhea
** test hypothesis that exercise induced amenorrhea was caused by increased energy utilisation
** an extra ~400kcal was provided to 4 monkeys that had experienced exercise induced amenorrhea for at least 3 menstrual cycles while implementing the same exercise schedule.
* Measurement of T3
** blood samples were taken to measure whether changes in reproductive function was linked to energy availability
It is unclear whether or not this methodology was the best approach as study was conducted in a small scale using non-human test subjects. They did, however, use an approach that measured variables in both the development and reversal of exercise induced amenorrhea to test their hypothesis and determine the primary cause.

## What were the basic results?

The study found the following key results:
* overfeeding led to a significant increase in energy intake (58%)
* Mean body weight increased during overfeeding period (6%)
* LH, FSH and E2 levels increase from late amenorrhea to surge
* significant negative correlation (r = -0.98; P < 0.024) between the calories consumed during the overfeeding period and the number of days until the LH surge
* no significant changes in body weight over development of amenorrhea
* LH and FSH decreased over development of amenorrhea
* During period of amenorrhea T3 levels decreased by ~20%
* During reversal period all 4 overfed monkeys had increased T3 levels

## What conclusions can we take from this research?

This study provides strong evidence that exercise induced amenorrhea is caused by a negative energy balance created by the increased energy expenditure of a regular, vigorous exercise schedule and low energy availability.
Spontaneous resumption of menstrual cycles in animals with exercise induced amenorrhea has not been witnessed in previous studies. It can be concluded that the primary cause of exercise induced reproductive dysfunction is energy cost in relation to exercise rather than physical or psychological stresses. This is because if any other factors had a significant role in the development of amenorrhea, caloric increase alone would not be enough to reverse the state of amenorrhea.
T3 levels decreased during the amenorrheic stage and dramatically increased during the overfeeding phase of the experiment and the reinstating of normal menstrual cycles.
The researchers have expanded on the findings of previous studies by including the extra experimental approach relating to the reversal of amenorrhea and how it can be achieved by increasing caloric intake.
More research into the involvement of T3 in changes in energy expenditure and the impact of metabolic efficiency on exercise induced reproductive dysfunction is needed for a greater understanding of the role that each has in mediating thefunction of the reproductive axis.

## Practical advice

With the increasing number of women participating in exercise and physical activity, if is becoming continually more important that women are aware of the potential risks associated with constant, vigorous exercise and a negative energy balance.
Exercise induced reproductive dysfunction can have long term effects if left untreated, so it is important that the athlete, coach and nutritionist are working together for prevention/treatment. This will include monitoring susceptible athletes and encouraging them to keep a diary so they are aware of any irregular cycles and providing information about energy balance.

## Further information/resources

* The Female Athlete Triad
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3435916/
* The Effects of Physical Exercise on the Female Reproductive System
https://www.researchgate.net/publication/257814328_Effects_of_physical_exercise_on_the_female_reproductive_system
* The Effects of Intense Exercise on the Female Reproductive System
file:///Users/emilycameron/Downloads/[14796805%20-%20Journal%20of%20Endocrinology]%20The%20effects%20of%20intense%20exercise%20on%20the%20female%20reproductive%20system.pdf

## References

* ↑ Williams NI, Helmreich DL, Parfitt DB, Caston-Balderrama A, Cameron JL. Evidence for a causal role of low energy availability in the induction of menstrual cycle disturbances during strenuous exercise training. The Journal of Clinical Endocrinology & Metabolism. 2001 Nov 1;86(11):5184-93.
* ↑ Warren MP, Perlroth NE. The effects of intense exercise on the female reproductive system. The Journal of endocrinology. 2001 Jul;170(1):3-11.
* ↑ Cannavò S, Curto L, Trimarchi F. Exercise-related female reproductive dysfunction. Journal of endocrinological investigation. 2001 Nov 1;24(10):823-32.
* ↑ Loucks AB, Vaitukaitis J, Cameron JL, Rogol AD, Skrinar G, Warren MP, Kendrick J, Limacher MC 1992 The reproductive system and exercise in women. Med Sci Sports Exerc 24:S288–S293
* ↑ Knuth UA, Hull MG, Jacobs HS 1977 Amenorrhea and loss of weight. Br J Obstet Gynaecol 84:801–807
* ↑ Vigersky RA, Andersen AE, Thompson RH, Loriaux DL 1977 Hypothalamic dysfunction in secondary amenorrhea associated with simple weight loss. N Engl J Med 297:1141–1145
* ↑ Caruana EJ, Roman M, Hernández-Sánchez J, Solli P. Longitudinal studies. Journal of thoracic disease. 2015 Nov;7(11):E537.
* ↑ Williams NI, Helmreich DL, Parfitt DB, Caston-Balderrama A, Cameron JL. Evidence for a causal role of low energy availability in the induction of menstrual cycle disturbances during strenuous exercise training. The Journal of Clinical Endocrinology & Metabolism. 2001 Nov 1;86(11):5184-93.
* ↑ Williams NI, Helmreich DL, Parfitt DB, Caston-Balderrama A, Cameron JL. Evidence for a causal role of low energy availability in the induction of menstrual cycle disturbances during strenuous exercise training. The Journal of Clinical Endocrinology & Metabolism. 2001 Nov 1;86(11):5184-93.
* ↑ Williams NI, Caston-Balderrama AL, Helmreich DL, Parfit DB, Nosbisch C, Cameron JL, 2001 Longitudinal changes in reproductive hormones and menstrual cyclicity in cynomolgus monkeys during strenuous exercise training: abrupt transition to exercise-induced amenorrhea. Endocrinology 142:2381–2389