Female Athlete Triad – Pathophysiology, Diagnosis and Treatment

he female athlete triad is a combination of menstrual dysfunction, low energy availability with or without an eating disorder, and decreased bone mineral density often seen in young women in competitive sports.

Classically female athlete triad was defined as consisting of disordered eating, amenorrhea, and osteoporosis.

In 2007, the inclusion criteria were broadened

• Disordered eating- replaced by low energy availability or without an eating disorder, the spectrum ranging from optimal energy to low energy
• Amenorrhea- Menstrual condition spectrum ranging from eumenorrhea to functional hypothalamic amenorrhea
• Osteoporosis – a spectrum ranging from “optimal bone health” to “osteoporosis”

Energy availability is the cornerstone on which the other two 2 components of the triad build upon. This component is thus key to correction.

Female athlete triad can have a significant impact on the health of the athlete. The full impact of this syndrome may not be realized until these women reach menopause when bone loss is accelerated.

Relative energy deficiency in sport” or “RED-S” is considered more accurate as it also describes the of health issues affected by decreased energy availability which include[metabolic rate, menstrual function, bone health, immunity, protein synthesis, cardiovascular and psychological health. This term is also to include men, who could also be affected by an imbalance in energy availability. But the term is not adopted yet.

Sports that have an aesthetic component ( ballet, or gymnastics) or have group classification based on weight (judo, or wrestling) have a higher prevalence of affected female athletes.

Majority of cases are diagnosed only after advanced symptoms become apparent. To diagnose milder cases, one needs a high index of suspicion.

In women who participate in sports that emphasize aesthetics or leanness, secondary amenorrhea can be as high as 69%, compared with 2% to 5% in the general population.

The prevalence of clinical eating disorders among female elite athletes ranges from 16% to 47%.

Pathophysiology

Reduced energy availability

It is defined as dietary energy intake minus exercise-energy expenditure. This could be due to
• Undereating
• Weight concerns

Disordered eating is the spectrum of behaviors ranging from not taking enough food to offset energy expenditure to preoccupation with eating and a profound fear of becoming fat.

These tend to each unrealistic weight and body fat goals dictated by their sport which is detrimental to their health.

Menstrual dysfunction

The spectrum ranges from normal menstrual function [eumenorrhe] to amenorrhea. Earlier amenorrhea was the criteria but present definition also will include a large portion of athletes who may have low estrogen levels but who still experience menstruation.

Menstrual dysfunction which may be present are

• Luteal suppression – short luteal phase, prolonged follicular phase, ovulation present, menstruation present
• Anovulation – low estrogen and progesterone, absent ovulation, irregular menses
• Oligomenorrhea
• Primary/secondary amenorrhea

Impaired bone health

It determined by BMD (or bone mineral content) and bone quality.

Bone quality cannot be measured as yet.

It refers to factors related to bone turnover rates

• Resorption versus formation
• Microarchitecture
• Time taken for maturation of the new bone matrix
• bone geometry and size).

This inability to measure may explain why some athletes with the same poor bone mineral density as their colleagues may suffer more fractures.

Dual-energy x-ray absorptiometry is used as a quantitative measure of bone health.
[more on BMD and scores]

T-score is used to gauge fracture risks for postmenopausal woman.

In athletes, therefore, Z-score is used for chronologic age.

Athletes with a Z-score 2 SDs below the mean are to be termed low bone density below the expected range for age.

But as athletes already have a higher BMD than nonathletes, an athlete with a BMD Z-score below -1.0 is recommended to get further work up.

The bones of the lower extremities, pelvis, and vertebrae are the ones most commonly affected by poor bone health in women with the female athlete triad, typically manifested by stress fractures or and frank fractures of these areas are the typical manifestations.

It is interesting to note that menstruating athletes gain approximately 2-4% of bone mass per year, whereas amenorrheic athletes tend to lose 2% per year.

Other physiologic dysfunction

Following conditions can occur concurrently with the female athlete triad

•  Anemia
• Chronic fatigue
• Increased risk of infection
• Esophagitis
• Electrolyte imbalance
• Slowing of the metabolic rate
• Decreased production of growth hormone
• Unfavorable lipid panels
• Endothelial dysfunction
• Reduced muscle protein synthesis
• Depression.

In addition, there is a possibility of long-term reproductive adverse effects.

Theories Behind Female Athlete Triad

There is a negative calorie balance. this energy drain disrupts the hypothalamic-pituitary-ovarian axis, resulting in decreased gonadotropin-releasing hormone (GnRH) pulsatility and low levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels.

This causes decreased estrogen production which causes menstrual dysfunction. The decreased estrogen levels, in turn, affect calcium resorption and bone accretion, causing decreased bone health.

Another theory considers the hormone leptin, which is secreted by adipocytes. It influences the metabolic rate, and levels are proportional to body mass index. It may be a significant mediator of reproductive function as studies have shown low levels of leptin correlating positively with amenorrhea and infertility.

Leptin receptors have been found on hypothalamic neurons involved in the control of GnRH pulsatility and in bone, which may also affect osteoblastic function.

Emotional stressors often lead to disordered eating and excessive training and may contribute.

Clinical Presentation

The athlete might be identified as at risk at health examination or might present with a stress fracture or menstrual disturbances.

A  multidisciplinary approach should be used. A detailed history is obtained to look for the contributing factors and conditions. Specific histories to be obtained are

• History of fractures
• Endocrine disorders history
  • Thyroid abnormalities
  • Panhypopituitarism
  • Diabetes
• Menstrual history
  • Age of menarche
  • Length of menses, and menstrual cycle
  • Any missed periods
  • Pregnancy
• Psychosocial history
  • Addiction history
  • Sexual or physical abuse
  • Depression/Suicidal tendencies
  • Anxiety
  • Previous eating disorders
  • Recent trauma or illness
  • Change in coaches
  • Significant personal/academic events.
  • Lack of a familial or social support system
• Exercise history
• Nutritional intake assessment
• Current medications
  • Prescription medications
  • contraceptive medications,
  • Use of hormones

A complete screening physical examination should be performed which should include

• General physical examination
• Gynecological examination
• Psychological examination
• BMI Measurement

Causes of menstrual dysfunction and/or poor bone health and secondary physiologic issues should be looked forf the triad.

The diagnosis of the female athlete triad is largely clinical.

Diagnostic Considerations

• Hypogonadotropic hypoestrogenism
• Hypothalamic disorders
• Hyperthyroidism
• Luteal-phase inadequacy
• Nutritional deficiencies
• Gonadal dysgenesis or ovarian defects
• Pituitary disorders

Laboratory Studies

Obtain the following in a female suspected of having the female athlete triad

• Urine or plasma pregnancy test to rule out pregnancy
• Urinalysis to establish volume status
• Complete blood cell for anemia
• ESR and CRP to check inflammation or infection
• Complete metabolic panel
  • Liver function
  • Electrolyte levels
  • Kidney function
• Hormone levels
  • Thyroid panel
  • Follicle-stimulating hormone and luteinizing hormone [for pituitary and possible premature ovarian failure]
  • Prolactin test [pituitary function]
  • Testosterone and dehydroepiandrosterone
  • Estradiol levels

Imaging

X-rays

If the athlete presents with bone pain, as with a stress fracture, appropriate plain radiographs should be obtained.

Dual Xray Absorptiometry

Indication for DEXA are

• ?1 ‘High risk’ triad risk factors:
  • History of a DSM-V diagnosed ED
  • BMI ?17.5 kg/m², < 85% estimated weight, OR recent weight loss of ?10% in 1 month
  • Menarche ?16 years of age
  • Current or history of < 6 menses over 12 months
  • Two prior stress reactions/fractures, one high-risk stress reaction/fracture, or a low-energy nontraumatic fracture
  • Prior Z-score of <–2.0 (after at least 1 year from baseline DXA)
• ? 2 “Moderate risk” triad risk factors:
  • Current or history of DE for 6 months or greater
  • BMI between 17.5 and 18.5, < 90% estimated weight, OR recent weight loss of 5–10% in 1 month
  • Menarche between ages 15 and 16 years
  • Current or history of 6–8 menses over 12 months
  • One prior stress reaction/fracture
  • Prior Z-score between –1.0 and –2.0 (after at least 1 year
  • interval from baseline DXA)

In addition, following may be considered for DEXA

• A history of ?1 nonperipheral or ?2 peripheral long bone traumatic fractures (nonstress) should be considered for DXA testing if there are one or more moderate or high-risk triad risk factors.
• Athletes on medications for 6 months or greater that may impact bone (such as depot medroxyprogesterone acetate, oral prednisone, and others).

Follow up DEXA scans depend on the severity of disease, the success of treatment and the ongoing status of the athlete.

In case of concern, scans every 1-2 years may be necessary to evaluate the ongoing bone health of the athlete.

Other Imaging Studies

• MRI head for pituitary dysfunction
• Pelvic ultrasonography for ovaries
• Hand images for bone age.
• Bone for a suspected stress fracture,
• ECG when resting heart rate <50 beats/min.

Other Tests

Progesterone Challenge

It is used to determine if the uterine endometrium has been primed with estrogen and thus is ready to be shed, as in normal menstruation. 5 or 10 mg of oral progesterone is given for 10 days to induce menstrual bleeding.

Lack of bleeding indicates that the uterine endometrium has not been adequately exposed to estrogen since the last menses.

Endometrial Biopsy

It is done to determine the stage of growth of the endometrial tissue and, thus, the effects or presence of estrogen and progesterone.

Treatment of Female Athlete Triad

Lack of Available Energy

The treatment has to be approached by multiple team members, given the complexity of the issue.

The cornerstone of the female athlete triad is decreased energy availability. It is the key element to be corrected.

It is done by increasing caloric intake and/or decreasing energy expenditure.

However, the participation of the athlete is very important.

In case non-pharmacological approach fails, antidepressant medication may be useful in aiding treatment.

Correction by dietary and habit changes would also correct menstrual dysfunction and BMD.

Nonpharmacological therapy is considered for one year.

Lack of response to therapy has been defined as

• A clinically significant reduction in z-scores after at least 1 year of nonpharmacological therapy or
• The occurrence of new clinically significant fractures during nonpharmacological treatment over the course of 1 year

BMD

For BMD, indications for drug treatment are

• after lack of response to at least one year of nonpharmacological therapy
  • Z-scores less than or equal to -2.0 with a clinically significant fracture history
  • Z-scores between -1.0 and -2.0 with a clinically significant fracture history plus greater than or equal to 2 additional triad risk factors [or even1 according to some authors]

The drug treatment considered is

• Transdermal estradiol replacement with cyclic progesterone
• Calcium supplementation [1300-1500 mg/day]
• Vitamin D supplementation [1500 and 2000 mg/day]

Symptomatic treatment for other musculoskeletal conditions may be done.

Surgery is usually not indicated except in some fractures

Hormone replacement therapy and oral contraceptive pills are not commonly used in athletes with the female athlete triad.

Restoration of menstrual function

If lack of energy availability is corrected by meeting the calorie requirement, the menstrual function gets corrected.

The availability of energy will restore gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) pulsatility, as well as menstruation.

If the nonpharmacologic treatment does not work, transdermal estradiol with cyclic progesterone has been found to be helpful.

Bisphosphonates are indicated in postmenopausal athletes with severe osteoporosis.

Prevention of Female Athlete Triad

Female athlete triad is difficult to diagnose, hence its prevention becomes quite significant.

Regular screening and identification of at-risk athlete is one strategy.

The preparticipation physical examination presents an ideal opportunity to screen all female athletes for signs or symptoms of the female athlete triad.

Athletes should be encouraged to report missed periods or scanty periods because they might indicate underlying issues. Therefore athletes need to be educated on the issue.

Misconceptions like amenorrhea is a sign of hard work should be addressed.

Physicians need to keep a stronger vigil and high index of suspicion too.

Prognosis

For many, the long-term prognosis is good.

Few athletes with the female athlete triad require inpatient treatment. Some may die from their disease or serious complications, such as cardiac arrhythmias.

Others may have significant long-term morbidity affecting them later in life.

References

• Sabatini S. The female athlete triad. Am J Med Sci. 2001 Oct. 322(4):193-5.
• Sanborn CF, Horea M, Siemers BJ, Dieringer KI. Disordered eating and the female athlete triad. Clin Sports Med. 2000 Apr. 19(2):199-213.
• Nichols JF, Rauh MJ, Lawson MJ, Ji M, Barkai HS. Prevalence of the female athlete triad syndrome among high school athletes. Arch Pediatr Adolesc Med. 2006 Feb. 160(2):137-42.
• Thein-Nissenbaum J. Long term consequences of the female athlete triad. Maturitas. 2013 Jun. 75(2):107-12
• Committee on Adolescent Health Care. Committee Opinion No.702: Female Athlete Triad. Obstet Gynecol. 2017 Jun. 129 (6):e160-e167.