A healthy and regular menstrual cycle is considered a vital sign of good health for premenopausal women. A normal menstrual cycle should occur every 25-35 days, (give or take a few days on either end), with the average cycle length falling at about 28 days. The length of the period can range from 3-7 days and the flow can be light, moderate, or heavy within a single menstrual cycle. A woman’s experience of her menstrual cycle may be unique to her, and what constitutes normal can have a broad range. Most importantly, each woman should be familiar enough with her own cycle to know if something has changed and when it is appropriate to seek help. One such situation would be the complete loss of a menstrual cycle for 3 months or more.
Amenorrhea is defined as a complete absence of menses in a woman of reproductive age. Primary amenorrhea is the failure to reach menarche (the first menstrual cycle) during normal development and is diagnosed when there is no history of menstruation by the age of 15 or 3 years after thelarche (breast bud development, which usually occurs around age 10). Secondary amenorrhea is defined as the absence of menses for ≥3 months in a woman with previously regular menstrual cycles or ≥6 months in any woman with at least one previous spontaneous menstruation (1).
Primary amenorrhea can be classified into general groups: sexual development abnormalities, obstruction to menstrual flow, ovarian insufficiency, hypothalamic or pituitary disorders, and other endocrine gland disorders. Secondary amenorrhea may be caused by hormonal disturbances, physical damage to the endometrium preventing its growth, or a physical obstruction that prevents menstrual outflow (2).
Functional hypothalamic amenorrhea
Functional hypothalamic amenorrhea (FHA) is the most common cause of secondary amenorrhea in women of childbearing age and is related to low energy availability due to psychological stress, excessive exercise, disordered eating, or a combination of all three. FHA is responsible for approximately 30% of secondary amenorrhea and 3% of primary amenorrhea. The diagnosis of FHA is usually determined by exclusion after ruling out other etiologies of amenorrhea and is characterized by low serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (3,4).
FHA results in hypogonadotropic hypogonadism and is presumed to be a consequence of functional disruption of the pulsatile hypothalamic gonadotropin-releasing hormone (GnRH) secretion, leading to reduced levels of FSH and LH that regulate the ovarian cycle. Reduced levels of FSH and LH result in the absence of normal follicular development, anovulation, and low serum estradiol. Variable neuroendocrine patterns of LH secretion are also reported, including reduced frequency and/or amplitude of LH pulses (5,6).
Genetic factors that contribute to FHA
Most young women experience stress in one form or another, and given societal pressures, some will undereat and overexercise to maintain a certain body weight and fitness level. Many young women who are involved in athletics are required to maintain a level of fitness that can lead to the “female athlete triad”, in which low energy intake, high energy output, and stress result in loss of the menstrual cycle and reduced bone density. However, not all women who are under stress, have a restricted diet, and exercise to the point of weight loss will develop FHA. There is considerable variability in the degree of weight loss and/or physical exertion necessary to induce FHA (4).
The predisposition of some women for developing FHA may be due to genetic variants associated with GnRH deficiency, where individual mutations may contribute to a greater or lesser susceptibility to the various stressors associated with FHA. Kisspeptin is a neuropeptide that participates in the release of gonadotropin-releasing hormone (GnRH), which regulates the HPO axis. Kisspeptin is released by hypothalamic nuclei, but its release can be disrupted when a woman’s energetic balance is decreased – not enough calories consumed and too many calories burned. Kisspeptins are a group of proteins encoded by the KISS1 gene discovered in Hershey, PA, in 1996 (hence the name KISS after Hershey’s Kiss). Mutations that inactivate the KISS1 gene are linked to FHA, while activating mutations may lead to premature puberty (7,4).
The effects of stress on the HPO axis
Stress can come in various forms, whether it is psychological or physiological. The stress response can be viewed as a survival mechanism that keeps us alive until we can escape whatever might be causing the stress. Reproductive function is not essential for survival and requires a large amount of energy, so it is understandably suppressed during times of great stress (7).
Various forms of stress can reduce the formation of kisspeptin by inhibiting the expression of the KISS1 gene. Corticotrophin-releasing hormone (CRH) from the hypothalamus, corticotropin (ACTH) from the pituitary, and cortisol from the adrenal glands produced in response to stress, directly inhibit the production of kisspeptin as well as GnRH. CRH inhibits the pulsatile frequency of GnRH, while cortisol inhibits reproductive function at the hypothalamus, pituitary, and uterine levels (4).
Gonadotropin inhibiting hormone (GnIH), produced in the hypothalamus, suppresses the synthesis and release of GnRH, FSH, and LH. GnIH increases in response to acute and chronic stressors further leading to dysregulation of the HPO axis and suppression of reproduction. Experimental trials revealed an increase in GnIH and a decrease in GnRH when corticosterone was administered. Kisspeptin and GnIH are two neuropeptides that provide a chemical link between the effects of stress and inhibited reproduction (7,4).
Meczekalski et al. conclude that stress-induced changes are the main driver of reproductive inhibition in women with FHA. Compared to healthy controls, FHA patients were characterized by lower serum kisspeptin levels and higher serum CRH. Stress-related FHA highlights the complex interplay between the HPA and HPO axes. Receptors for CRH and cortisol are expressed on kisspeptin neurons in the hypothalamus indicating that kisspeptin functions as a signaling bridge between the HPA and HPO axes (7).
Other factors that influence kisspeptin levels include body mass index, in which low body mass correlates with lower levels of kisspeptin. Leptin, a peptide hormone that signals satiety, is positively correlated with kisspeptin and GnRH in that leptin stimulates the expression of the KISS1 gene. Ghrelin, another peptide hormone that opposes the effects of leptin by stimulating hunger, tends to increase in states of energy deficiency, or lack of satiety, and tends to suppress the hypothalamic expression of the KISS1 gene and impairs GnRH secretion (7,4).
Additionally, energy-deficient states can lead to dysfunction within the hypothalamic-pituitary-thyroid (HPT) axis, resulting in hypothyroidism as a means to slow metabolic rate for self-preservation. While thyroid-stimulating hormone (TSH) may remain stable, triiodothyronine (T3) decreases, and thyroxine (T4) will be normal or low. A state of hypothyroidism can ultimately impair bone formation and remodeling at a time when bone mineral density should be reaching its peak (4,6).
Diagnosis of FHA
In addition to measuring serum levels of gonadotropins (FSH, LH), estradiol, and ruling out pregnancy, an assessment for FHA should include a gynecological exam and a thorough history that includes evaluation of diet and exercise habits, recent weight loss, and perception of stress level. Additional bloodwork to rule in or out any possible contributors or causes of amenorrhea might include a complete thyroid panel, prolactin level, androgen level, and anti-Mullerian hormone as a measure of ovarian reserve. Imaging studies may also be warranted to rule out ovarian cysts, structural anomalies, and pituitary or hypothalamic conditions (4,6).
In a clinical setting, a GnRH stimulation test would result in a positive response of FSH and LH. In younger women, this test might be appropriate to differentiate delayed puberty from FHA. The administration of a progestin challenge is not useful in the diagnosis of FHA because the withdrawal bleed is scant or nonexistent due to low estrogen (8).
Salivary testing to measure the daily rhythm of cortisol can provide objective data revealing the physiological response to stress. ZRT offers several salivary tests to measure cortisol rhythm, sex hormones, and DHEA. Dried blood spot samples can be used to measure sex hormones, gonadotropins (FSH, LH), and thyroid function, providing additional data to support an accurate evaluation of the causes and contributors to the development of FHA. Further evaluation for mood disorders related to depression and anxiety should also be considered, as these conditions often coexist as a contributing factor to the development of FHA and as a result of hypoestrogenism. Dried urine testing for neurotransmitters can further reveal imbalances that may be contributing to stress patterns and mood disorders.
Short- and long-term consequences of FHA
The loss of a regular menstrual cycle in a previously menstruating woman is not without consequences. Adequate levels of estrogen are needed to support fertility, bone health, cardiovascular health, and brain health.
Fertility
The dysfunction of the HPO axis results in anovulation and infertility. If a woman with FHA experiences spontaneous ovulation and conceives, there is a tendency toward increased risk of miscarriage or preterm labor. Low estrogen in women with FHA can lead to changes in vaginal mucosa and pH, predisposing to genitourinary tract infections. The reproductive and hormonal issues associated with FHA are reversible and can resolve over time after the return of hormone levels and normalization of the menstrual cycle (4).
Cardiovascular System
A low estrogen state can contribute to cardiovascular disease in women. This relationship has been well-established in studies on menopausal women who develop hypertension and cardiovascular disease in menopause. Low estrogen leads to endothelial dysfunction, dysregulated activity of nitric oxide (which is associated with vasodilation), and excessive activation of the renin-angiotensin system – all three states contribute to the development of hypertension. Additionally, low estrogen contributes to changes in the lipid profile, resulting in higher total cholesterol, triglycerides, and LDL cholesterol (4,6).
Bone Health
Hypoestrogenism causes changes in bone turnover with decreased bone formation, and increased bone resorption. Women who experience FHA may end up with lower bone mineral density due to reduced nutritional and energy status, low estrogen, high cortisol, and excessive exercise. Stress fractures are more common in women who experience amenorrhea, especially if it is associated with intense exercise. Women with FHA who exercise intensely in adolescence and young adulthood have a lower bone mineral density Z-score in the lumbar spine when compared to menstruating women. Bone mineral density can be restored once hormone levels normalize or through supplementation with estrogen (4,6).
Brain health and state of mind
Going through menopause is not something that a woman can opt out of, and they know all too well the effects of low estrogen on brain function and mood. Women with FHA experience psychological symptoms similar to women in menopause because of hypoestrogenism. Estrogen modulates the activity of many neurotransmitters and neuromodulators in the brain such as serotonin, norepinephrine, acetylcholine, and dopamine. Poorly managed stress is a contributor to FHA but may also result from the loss of estrogen and its effects on brain health and mood. Additionally, women with FHA tend to have a higher rate of perfectionism when compared to eumenorrheic peers, which adds a degree of stress (6).
Treatment of FHA
Lifestyle
Addressing lifestyle and stress management should be the first approach to treating FHA. Increasing nutrition in the form of high-quality food and sufficient calories, reducing and managing stress effectively, and moderating exercise are key to normalizing menstrual cycles and ovarian activity. If a woman is underweight, a moderate weight gain of as little as five pounds may make the difference between amenorrhea and normal cycles. Attaining a normal BMI (body mass index) of at least 18.5 aids in recovery from FHA and increases fertility (4,6,8).
Psychological counseling
Anxiety and other mood disorders often coexist with FHA and may be a contributing factor. Evaluating young women for eating disorders is also warranted if body weight is very low and there are signs of disordered eating, unhealthy and rigid dietary habits, and body dysmorphia. Guidance on managing stress through cognitive behavioral therapy (CBT), family counseling, and relaxation techniques can be useful tools that have a positive effect across a woman’s lifetime (4,6,8).
Hormones
If menstrual cycles have been absent for 6-12 months and underlying lifestyle factors have been addressed with other potential causes of amenorrhea ruled out, replacement of hormones may be necessary to prevent further issues associated with hypoestrogenism. The use of cyclic transdermal estradiol and oral progestogen therapy is commonly used to address FHA and has been demonstrated to improve lumbar and hip bone density. Transdermal estrogen has a greater effect on bone density because it does not decrease the IGF-1 level, which is needed to build bone whereas, oral contraceptives decrease IGF-1. The use of oral contraceptives is discouraged for the hormonal treatment of FHA as it has a continued suppressive effect on ovulation (4,8,6).
The use of hormones can also have a positive effect on cognitive function, mood, and weight gain. Low-dose estrogen may positively modulate the spontaneous restart of gonadotropin release. The use of low-dose estrogen provides positive feedback to the hypothalamus and pituitary and may restore the HPO axis by initiating the maturation of ovarian follicles and promoting the thickening of the endometrium (8, 4).
Botanicals and supplements
First and foremost, a healthy energy status needs to be maintained with adequate nutrition to support the return of a menstrual cycle, as energy deficiency is a key underlying cause. Botanicals and supplements are secondary to a healthy diet with sufficient calories, reduced exercise, and management of stress. Introducing a high-quality multivitamin, minerals, essential fats, and vitamin D can help to build and restore nutritional reserves. Botanicals that support ovulation and the HPO axis in general, might only be effective if estrogen is restored by addressing the underlying cause or through initial cyclical supplementation of estrogen.
Figure 1. Treatment of women with FHA includes a reduction of excessive exercise, dietary evaluation and psychological support to reduce stress, an enhancement of behavioral change and an increase of energy availability. Estrogen replacement therapy may be considered after 6 to 12 months of nutritional, psychological, and exercise-related interventions in those with low bone density and/or evidence of skeletal fragility. Assisted reproductive technologies may be considered in patients wishing to conceive. Low-dose estrogen use in patients with FHA is still under study. (8)
In summary
FHA is a functional disorder leading to amenorrhea in previously menstruating women. The dysfunction that leads to FHA can appear simple on the surface, but it can reflect a deeper psychological pathology that should be addressed with care. Body image issues are perpetuated in young women through images viewed on various media platforms. Popular influencers on social media may promote extreme diets and exercise programs that feed this dysfunction. Eating disorders and body dysmorphia are nothing new, but the platforms that influence young women have grown excessively through access to social media.
Young women who might follow advice acquired on these platforms may be well-intentioned and trying to improve their health and fitness level. While this is a noble goal that can have lifelong benefits, the complete loss of menstruation is a signal – a vital sign – that something is off. Consulting with an educated professional on caloric needs relative to energy output, along with strategies to effectively manage stress, can be a wise investment in a young woman’s health and well-being that will serve her well throughout the phases of her reproductive life.
References
- Gasner, Adi, and Anis Rehman. “Primary Amenorrhea.” StatPearls, StatPearls Publishing, 2024. PubMed.
- Lord, Megan, and Manjusha Sahni. “Secondary Amenorrhea.” StatPearls, StatPearls Publishing, 2024. PubMed.
- Shufelt, Chrisandra L., et al. “Hypothalamic Amenorrhea and the Long-Term Health Consequences.” Seminars in Reproductive Medicine, vol. 35, no. 3, May 2017, pp. 256–62. PubMed Central.
- Podfigurna, Agnieszka, and Blazej Meczekalski. 2021. "Functional Hypothalamic Amenorrhea: A Stress-Based Disease" Endocrines 2, no. 3: 203-211.
- UpToDate. #H1145087543. Accessed 17 Apr. 2024.
- Saadedine, Mariam, et al. “Functional Hypothalamic Amenorrhea: Recognition and Management of a Challenging Diagnosis.” Mayo Clinic Proceedings, vol. 98, no. 9, Sept. 2023, pp. 1376–85. ScienceDirect.
- Meczekalski, Blazej, et al. “Stress, Kisspeptin, and Functional Hypothalamic Amenorrhea.” Current Opinion in Pharmacology, vol. 67, Dec. 2022, p. 102288. ScienceDirect.
- Battipaglia, Christian, et al. “Low-Dose Estrogens as Neuroendocrine Modulators in Functional Hypothalamic Amenorrhea (FHA): The Putative Triggering of the Positive Feedback Mechanism(s).” Biomedicines, vol. 11, no. 6, June 2023, p. 1763. PubMed Central.
