
June 10, 2024
Healthy Eating Week
Functional Hypothalamic Amenorrhea Clinical Practice Guidelines: A Review
By: Haley Wissler
Director’s Note: During Healthy Eating Week, we feature the latest update on functional hypothalamic amenorrhea (FHA) summarized by Haley Wissler, a former FACTS elective participant. Commonly associated with disordered eating among young women, effective management of FHA requires healthy eating habits – not necessarily eating less, but eating a balanced diet. This summary of the 2017 Endocrine Society Clinical Practice Guideline published in The Journal of Clinical Endocrinology & Metabolism [2] discusses evaluation, diagnosis, and treatment of FHA. FACTS elective student Wissler notes the guidelines could be expanded to reflect the utility of fertility awareness-based methods (FABMs) for cycle charting to track patient recovery and facilitate earlier diagnosis. To learn more about FABMs and/or share information with friends or colleagues, please check out our FACTS webinars available on demand.
Background
Approximately 3-4% of women experience amenorrhea (three months without menstruation) not due to pregnancy, lactation or menopause. Functional hypothalamic amenorrhea (FHA) accounts for 20-35% of all cases of secondary amenorrhea and 3% of primary amenorrhea cases. [1] A woman with FHA experiences chronic anovulation without an identifiable organic cause, with the condition often linked to stress, weight changes, undernutrition or excessive exercise. This leads to a reduced gonadotropin-releasing hormone (GnRH) drive in the hypothalamus, decreasing the LH pulse frequency, and preventing follicular development and ovulation. Long term, untreated FHA can lead to delayed puberty and infertility as well as loss of bone mineral density (BMD), and other consequences of chronic low estrogen levels.
“A woman with functional hypothalamic amenorrhea (FHA) experiences chronic anovulation without an identifiable organic cause, with the condition often linked to stress, weight changes, undernutrition or excessive exercise.”
With the risk of long-term complications, it is important to recognize and treat FHA in a timely manner. Most adolescents and women experience at least 6 months of amenorrhea before a diagnosis is made. FHA is a diagnosis of exclusion, which makes it even more challenging to diagnose. To establish evidence-based guidelines, the American Society for Reproductive Medicine, the European Society of Endocrinology, and the Pediatric Endocrine Society collaborated to compile a set of clinical practice guidelines for the diagnosis and treatment of FHA.
Evaluation and Diagnosis
In an adolescent or woman with a menstrual cycle longer than 45 days or with three or more months of amenorrhea, FHA should be ruled out. While adolescents can have hypothalamic-pituitary-ovarian (HPO) axis immaturity leading to long, irregular cycles, their menstrual cycles are not typically greater than 45 days. The evaluation for possible FHA starts with a thorough history focused on diet, eating disorder history, fracture history, exercise patterns, weight changes, mood, stressors, and menstrual cycle history. Assessing for attitudes of perfectionism or the need for social approval is also important, as well as assessing for family history of eating disorders and/or reproductive disorders.
If FHA is suspected based on the history, a thorough evaluation should be done to rule out other causes of anovulation. However, FHA may co-exist with other reproductive disorders such as polycystic ovary syndrome (PCOS), so it is important to keep it on the differential diagnosis. Clinicians should start with a physical and gynecologic examination, a pregnancy test, and general screening labs, such as a CMP and CBC. Endocrine labs should include thyroid studies, androgen levels, prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), and Anti-Müllerian hormone (AMH). Psychological stressors and disorders are common triggers for FHA, so all patients with suspected FHA should be screened for underlying mental health concerns.
“If FHA is suspected based on the history, a thorough evaluation should be done to rule out other causes of anovulation … (and) all patients with suspected FHA should be screened for underlying mental health concerns.”
For women with anovulation longer than six months, a baseline bone mineral density scan using dual-energy X-ray absorptiometry (DEXA) may be indicated. Adolescents and women are at greatest risk of loss of BMD or inability to reach peak BMD in adulthood. For this reason, patients with suspected or known undernutrition, energy deficits or skeletal fragility will benefit from a DEXA scan. Clinicians should also consider a baseline DEXA scan for patients with FHA and underlying PCOS.
Treatment
Most treatments for FHA center around lifestyle changes that reduce stress, improve nutrition, and decrease exercise. For most patients, this means gaining weight. As there can be psychiatric comorbidities in these patients and various perceptions and attitudes about gaining weight, cognitive behavioral therapy by a trained therapist may facilitate their recovery. Patients with FHA who have severe bradycardia, hypotension, orthostasis, and/or electrolyte imbalances will likely require hospitalization for initial stabilization.
“Most treatments for FHA center around lifestyle changes that reduce stress, improve nutrition, and decrease exercise. As there can be psychiatric comorbidities …cognitive behavioral therapy by a trained therapist may facilitate their recovery.”
For those without a return of menses despite adequate lifestyle modifications, short-term transdermal E2 therapy with cyclic oral progesterone may hasten its return. However, oral contraceptive pills (OCPs) are not recommended for the sole purpose of regaining menses or improving bone mineral density. OCPs can mask the return of spontaneous menses and may not improve bone mineral density if the energy deficit continues.
For those wishing to conceive, weight gain and the return of menses will improve fertility in some patients. Women who continue to experience infertility require a complete infertility evaluation. Low maternal weight is a risk factor for poor fetal outcomes. For this reason, prior to ovulation induction in women with FHA, their body mass index (BMI) should be at least 18.5 and energy deficits must be appropriately corrected. Ovulation induction for women with FHA may include pulsatile GnRH or gonadotropin therapy. Clomiphene may also be considered in women who have sufficient endogenous estrogen.
Charting the Cycle
While not explicitly mentioned in the 2017 clinical practice guidelines for FHA, fertility awareness-based methods (FABMs) of cycle charting are powerful tools to aid in diagnosis and monitor improvement in these patients. The longer anovulation lasts, the longer it takes to reverse and the higher the possibility for bone density loss or an inability to reach her peak bone mass. Unfortunately, most adolescents and young women with FHA have amenorrhea for 6 months or longer prior to diagnosis.
Yet, a woman who tracks her cycle is more likely to be aware of its length and how long she goes without ovulating. Similarly, cycle charting during recovery from FHA-induced anovulation means she can track the length of her cycles, identify when they normalize, and uncover signs pointing to a coexisting reproductive health problem that was masked by FHA. For instance, nearly 50% of patients with the non-hyperandrogenic PCOS phenotype may have FHA, and charting the menstrual cycle may expedite diagnosis of this phenotype and treatment of any related cycle abnormalities.
“Cycle charting during recovery from FHA-induced anovulation … (can help) uncover signs pointing to a coexisting reproductive health problem that was masked by FHA… (such as) non-hyperandrogenic PCOS.”
Conclusion
Functional hypothalamic amenorrhea is an important cause of anovulation in adolescents and women. A thorough evaluation should be completed in patients with suspected FHA to rule out other disorders, while remembering that FHA can be a comorbid condition with other reproductive health problems. Treatment includes behavior modifications and weight gain, though women wishing to conceive may require further evaluation and ovulation induction beyond adequate treatment of FHA. The use of FABMs for cycle charting could be a new way to support earlier diagnosis of FHA and monitor improvement.
References
[1] Meczekalski B, Katulski K, Czyzyk A, Podfigurna-Stopa A, Maciejewska-Jeske M. Functional Hypothalamic Amenorrhea and Its Influence on Women’s Health. Journal of Endocrinological Investigation. 2014;37(11):1049-1056. doi:https://doi.org/10.1007/s40618-014-0169-3.
[2] Gordon CM, Ackerman KE, Berga SL, et al. Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism. 2017;102(5):1413-1439. doi:https://doi.org/10.1210/jc.2017-00131.
ABOUT THE AUTHOR
Haley Wissler
Haley Wissler is a fourth-year medical student at Penn State College of Medicine in Hershey, PA. She completed her undergraduate education at Temple University in Philadelphia, PA. She plans to pursue residency in pediatrics and hopes to use FABMs to teach adolescents about the menstrual cycle and to support early diagnosis of reproductive health problems.