Functional Hypothalamic Amenorrhea

Functional hypothalamic amenorrhea (FHA) is one of the most common causes of secondary amenorrhea, accounting for 20-35% of cases according to the American Society of Reproductive Medicine. The loss of menstrual periods in FHA is due to disturbances in the hypothalamic-pituitary-ovarian axis, typically in response to stress, caloric restriction, weight loss and/or excessive exercise. These stressors lead to impairment of GnRH secretion from the hypothalamus and decreased gonadotrophin (LH, FSH) secretion from the pituitary in response.

A key feature seen in FHA is activation of the hypothalamic-pituitary-adrenal (HPA) axis. Increased corticotropin-releasing hormone (CRH) secretion from the hypothalamus results in increased adrenocorticotrophin (ACTH) release from the pituitary and cortisol release from the adrenal glands. Ultimately, these alterations in HPA axis hormones are associated with reduced GnRH secretion from the hypothalamus, which affects the menstrual cycle.

Other symptoms associated with FHA in addition to irregular or absent menstrual cycles include low libido, depression, anxiety, feeling cold, and fatigue.

Diagnosis

FHA can be considered in women who have had amenorrhea for at least 6 months. It is a diagnosis of exclusion; other endocrine disorders and organic causes of must first be ruled out before FHA can be diagnosed. Endocrine testing will often reveal hypogonadotropic hypogonadism in patients with FHA. This means that gonadotrophs (LH, FSH) and ovarian hormones (estradiol) are low. However, due to fluctuations in hypothalamic function, women might sometimes have normal levels of gonadotrophs. To help identify the source of low gonadotrophs – hypothalamus or pituitary – a GnRH stimulation test can be used. Exogenous GnRH is given and then LH and FSH are measured. If this test is positive, meaning LH and FSH are produced in response to GnRH, it identifies the hypothalamus as the source of the low gonadotrophs, not the pituitary. To rule out a disease of the hypothalamus, like neoplasms or sarcoidosis, imaging can sometimes be helpful.

PCOS vs FHA

As we have already discussed, there can be many reasons for irregular or missed menstrual cycles. Two of the underlying causes of amenorrhea, PCOS and FHA, can sometimes be difficult to differentiate. Typically PCOS is related to insulin resistance and hyperandrogenism and presents with hirsutism and weight gain or difficulty losing weight. In FHA, menstrual cycles are irregular due to decreased signals from the brain. Typically FHA presents in those who are undereating or overexercising or both. However, the confusion comes into play when patients have atypical presentations – for example a very thin person may present with PCOS and a woman of normal weight or who has difficulty losing weight may present with FHA due to emotional stress. Incomplete work-ups can also lead to misdiagnosis because both PCOS and FHA can present with polycystic ovaries and anti-mullerian hormone (AMH) can be elevated in both conditions. To further complicate matters, patients can have both PCOS and FHA at the same time. A study published in the American Journal of Obstetrics and Gynecology in 2016 found that approximately 10% of women with FHA may have coexisting PCOS. This is why it is especially important to get detailed histories and order thorough endocrine testing to make sure we have the complete picture. Although both conditions cause irregular cycles and infertility, they each have separate long term health risks – PCOS with increased risk of insulin resistance and metabolic syndrome; FHA with increased fracture risk. In order to manage patients’ care appropriately it is important to get a correct diagnosis.

Female Athletes and Amenorrhea

FHA is particularly prevalent among female athletes. In addition to lower body weights/body fat percentages, it is thought that mental stress and heavy exercise also contribute to higher rates of amenorrhea in female athletes. Women who sustain heavy exercise loads over long periods of time sustain an energy deficit (calories consumed vs calories burned). The body may compensate for this deficit by decreasing metabolic rate and thereby disrupting the menstrual cycle. Because the metabolic rate is depressed, some women may maintain normal body weights despite the negative energy balance and loss of menstrual cycle.

The term “female athlete triad” refers to a syndrome with three interrelated conditions: menstrual dysfunction, low bone mineral density and low energy availability, with or without disordered eating. Athletes often function under the misconception that it is normal to lose your menstrual cycle. It is important to remember that the loss of menstrual can be a red flag that there are endocrine and metabolic imbalances at play.

Treatment

Fertility treatments to induce ovulation will look similar regardless of whether a patient has FHA or PCOS. Treatments to help address the underlying cause of dysfunction, however, will look very different and that is why a proper diagnosis is so important. Lifestyle modifications that would help insulin resistance in patients with PCOS would actually be counterproductive in FHA. In FHA, behavioral modification is important to improve the energy imbalance. These modifications could include increasing caloric intake, improving nutrition, and/or decreasing exercise. For patients with disordered eating or body dysmorphia, cognitive behavioral therapy (CBT) is warranted. CBT and stress management techniques is also important for patients with FHA due to high emotional stress.

Although in FHA the lifestyle modifications are most important, herbs can also be helpful as part of a holistic approach. Your doctor can recommend specific adaptogenic herbs and reproductive tonics to help support the HPA and HPG axes.