Hypothalamic Amenorrhea

Symptoms and Causes of Functional Hypothalamic Amenorrhea (FHA)

File photo | Credit: NICHDOpens in new window Functional hypothalamic amenorrhea (FHA) is the absence of menstrual cycles associated with high levels of physiological and psychological stress ranging from weight loss to maladaptive behavior and coping skills.

FHA is caused by a suppression of the hypothalamic-pituitary-ovarian (HPO) axis. The term “functional” indicates that the lack of menstrual cycles is due to improper functioning of the hypothalamic-pituitary-ovarian axis rather than due to an anatomic (organic) problem.

FHA entails a significant impact on ovarian function with hypoestrogenism and the sequent absence of a regular menstrual period persisting for more than 3 – 6 months in women who previously had regular cycles.

According to epidemiological data, in Europe and USA FHA accounts for 20 – 35% of cases of secondary amenorrhea, rising to be one of the most common reproductive disorders in women of childbearing age.

Among adolescent girls, the prevalence of FHA is approximately 15 – 48% of secondary amenorrhea diagnoses, but that may be underestimated due to the difficulty in differentiating from the instability of hypothalamic-pituitary ovarian (HPO) axis during puberty. However, once the menstrual pattern is assumed, the approach for the diagnosis of amenorrhea does not differ from that of adults.

FHA has been found to be related to the suppression of the HPO axis; these dysregulations of the HPO axis in FHA seemed not to be caused by any identifiable organic disease or anatomic factor, while they were found to be associated with stress, weight loss, and/or excessive physical exercise. Based on these eliciting factors, three variants of FHA have been established: weight loss-related, exercise-related, and stress-related.

As the cause of FHA does not seem organic but functional, the role of psychological factors can be decisive in assessing their impact on the onset and persistence of the disorder. In fact, a psychogenic component has been recognized in FHA since its first diagnostic formulation.

Considering weight loss-related FHA, evidence shows that psychological factors interact with significant physiological changes, metabolic alterations, and endocrinological aberrations, contributing to the persistence of FHA. Indeed, women with FHA reported more deranged eating attitudes, restrictive eating behavior, and bulimic symptoms than comparison. Thus, women with dysfunctional eating attitudes are at higher risk for menstrual problems and infertility.

As it is widely known, decreased food intake causes a shortage of energy, which leads the body to economize and thus suspend those functions not necessary for survival (such as menstruation). All these features are also present more severely in patients with an eating disorder, so it is essential to make an appropriate differential diagnosis.

Likewise, exercise-related amenorrhea is a frequent clinical condition among athletes, particularly those involved in elite sports and aesthetic disciplines, such as artistic skating and gymnastics.

Several psychological and behavioral factors have been identified as contributing to the high prevalence of secondary amenorrhea in athletes. One of the main factors is high energy expenditure associated with many athletic activities, which can lead to energy deficits and disrupt regular ovulatory cycles.

In addition, many athletes engage in disordered eating practices such as restricting food intake or engaging in extreme dieting to maintain leanness for optimal performance. Another potential factor is psychological stress associated with athletic training and overstated goals.

Neuroendocrinology and Pathophysiologyof FHA

Nutritional, physical, and psychological stressors affect the neuroendocrine control of the reproductive axis, which leads to the suppression of GnRH and, in turn, FHA. Specifically, neuropeptides such as corticotropin-releasing hormone (CRH), vasopressin, β-endorphin, leptin, ghrelin, allopregnanolone, and neuropeptide Y all may play a role in the pathophysiology of FHA.

CRH and vasopressin are released by the paraventricular nucleus of the hypothalamus and can inhibit GnRH release. CRH causes the release of ACTH from the pituitary which then stimulates cortisol secretion by the adrenal.

In vitro, and in vivo studies have shown that the release of GnRH can also be directly inhibited by CRH through its direct connections with GnRH neurons in the hypothalamus.

Cortisol is also coupled with a progesterone metabolite, allopregnanolone, in women with FHA as well as in healthy controls. However, woment with FHA experience a blunted allopregnanolone response to CRH. CRH stimulates the production of β-endorphin, an opioid peptide, and circulating levels of this peptide increase during intense exercise. In vitro studies have shown that β-endorphin inhibits GnRH release.

When β-endorphin release was blocked by naxolone, an opioid antagonist, GnRH levels increased. β-endorphin can also directly inhibit LH release. These findings suggest that β-endorphin mediates the action of CRH in suppressing GnRH.

In women with FHA, leptin (a protein produced by fat and implicated in reproductive function) levels are lower than in normal healthy women and the normal diurnal rhythm in leptin levels is also absent.

Low leptin levels are typical in amenorrheic women with low body fat, and leptin levels increase as body fat increases in women with FHA. Leptin levels increase significantly with every 1 kg increase in weight and are associated with the return of pulsatile LH release.

Moreover, hypoleptinemia may increase cortisol levels through activating the adrenergic pathway and CRH release. However, in women with FHA, estradiol levels are low (<20 pg/ml), and basal levels of neuropeptide Y are lower compared to healthy women.

Another hormone from the gut, ghrelin, opposes leptin function. Ghrelin inhibits GnRH secretion and is elevated in women with FHA, especially if these women have disrupted eating habits. Other peptides such as orexin A and kisspeptin that control GnRH release have been studied in women with FHA.

Possible Genetic Contribution to FHA

FHA is a condition that is similar to isolated hypogonadotropic hypogonadism and may have a genetic component as well. Both conditions refer to the amenorrhea due to the suppression of GnRH; however, hypogonadotropic hypogonadism has a genetic basis.

Mutations in genes for fibroblast growth factor receptor, prokineticin receptor 2, GnRH receptor, and KAL-1 are among those found in the hypogonadotropic hypogonadism and are also found in some women with FHA.

These genes are known to be loss-of-function mutants; for instance, expression of prokineticin receptor 2 on the cell surface and its signaling activity were significantly less in women with FHA than in healthy controls.

Furthermore, these genetic defects, particularly in the fibroblast growth factor receptor and prokineticin receptor 2, may contribute to the negative eating habits of women with FHA, as they alter eating behavior in animal models. Finally, the mutant GnRH receptor, KAL-1, and prokineticin receptor 2 are involved in the processes that lead to suppressed GnRH, altered LH activity, and absence of menstruation.

Diagnosis of FHA

The diagnosis of FHA has gained a firmer basis over the past few years. A thorough review of the medical history, including exercise and eating habits (e.g., binging or purging), must be conducted to identify the specific nutritional, physical, and psychological stressors that are present.

The physical examination must exclude all other possible medical reasons that would cause amenorrhea such as PCOS, adrenal hyperplasia, presence of an adrenal-secreting tumor, adnexal mass, an imperforated hymen, and Mullerian duct anomaly (i.e., absence of uterus). Signs of hirsutism, acne, male pattern baldness, clitoromegaly, voice changes, and vomiting (i.e., gingival abrasions, loss of dental enamel, parotid swelling) must also be examined.

Thus, levels of beta subunit of chorionic gonadotropin, thyrotropin, thyroxine, prolactin, follicle-stimulating hormone, free testosterone, and dehydroepiandrosterone sulfate must all be analyzed. Magnetic resonance images of the brain may also be used to determine conditions that might contribute to FHA.

The long-term negative health consequences of FHA include increased risk of cardiovascular disease (e.g., coronary artery disease), osteoporosis, increased risk for fractures, depression, dementia, and other psychiatric conditions. Both pharmacologic and non-pharmacologic therapies have been suggested for treatment of FHA.

Since the underlying causes of the FHA are thought to be dysfunctional attitudes and behaviors that result in stimulation of the hypothalamic-pituitary-adrenal axis and/or suppression of the thyroid function, cognitive behavioral therapy and hypotherapy are the best potential approaches for ameliorating this condition. Finally, increasing food intake and reducing stressful activities can be very effective in resotring menstruation.