Though functional hypothalamic amenorrhea (FHA) is classified in the WHO group I, it is considered as a hypogonadotropic hypogonadism related to a severe change of the pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus [10–12]. The disturbances of the hypothalamic-pituitary-ovarian axis in FHA may be very broad and includes from low to the complete absence of LH pulses in presence of normal level of FSH [12]. Because of this, there are low or very low estradiol plasma levels due to a reduced estradiol production in the ovary. The disturbed hypothalamic-pituitary-ovarian axis in FHA cases is associated typically with stress, weight loss, and/or excessive physical exercise and is one of the most common causes of secondary amenorrhea [12]. Depending on the triggering factor, there are three typologies of FHA: weight loss related, stress related, and exercise related [13]. However, it is relevant to state that though the trigger might be one of these three, usually all of them result to be tightly interconnected and regardless of the specific trigger, a complex state of hypoestrogenism, other endocrinologycal aberrations, and metabolic abnormalities due to FHA may affect the whole body homeostasis [14].

Classically, secondary amenorrhea is defined when there is at least an interval of 3 months of absence of menstruation, and usually occurs in approximately 3–5 % of women after menarche. FHA can be recognized in 20–35 % of secondary amenorrhea cases and in 3 % of FHA cases of primary amenorrhea that is in those cases where menarche does not occur at the right time but later than expected and no other cause is recognized as causal factor for such situation of delayed menarche [15]. Hypothalamic amenorrhea is very frequent among athlete women. In fact, it has been estimated [16] that approximately 50 % of women who exercise regularly experience menstrual disorders and approximately 30 % of them experience amenorrhea. Several of them show the triad of distorted eating, amenorrhea, and osteoporosis, first described in 1997 and is known as female athlete triad [17].

Functional hypothalamic amenorrhea can be differentiated from the other forms of primary or secondary amenorrhea on the basis of the anamnesis as well as from the assessment of low or very low gonadotropins and estradiol plasma levels [12]. In patients with FHA, the GnRH stimulation test shows the LH and FSH response, thus distinguishing FHA from pituitary diseases, where hypogonadism is also characteristic [13, 15]. Once the hypothalamic origin has been found, it is important to exclude eventual rare genetic and organic diseases such as Kallman syndrome (characterized by anosmia, specific mutations), Prader-Willi syndrome (with characteristic hyperorexia, obesity, retardation), and other rare syndromes with idiopathic hypogonadotropic hypogonadism [12, 15, 18]. Obviously, features such as delayed puberty, primary amenorrhea, and the presence of additional symptoms (anosmia, mental retardation, extreme obesity, facial dysmorphia, and malabsorption) are suggestive of congenital diseases [15, 18].

As it can be argued from what is reported in the previous section, FHA [19–21] is a model of reproductive dysfunction characterized by the fact that there is no organic disease to trigger it. Indeed, FHA is classically characterized by a hypoestrogenic condition as a result of several neuroendocrine aberrations, which occur after a relatively long period of exposure to a repetitive and/or chronic stressor(s) that negatively affect the neuroendocrine hypothalamic activity [10, 22] as well as the release of several hypophyseal hormones [23]. In these patients, the reproductive axis is severely impaired and both the opioid and dopaminergic systems are involved as potential mediators of stress-related amenorrhea in humans [24, 25]. As demonstrated in experimental animals, the EOPs exert an inhibitory effect on the episodic release of both GnRH and LH also in humans [26]. Naloxone infusion is able to induce the increase of LH plasma levels only during the late follicular and luteal phases of the menstrual cycle but not during the early follicular phase [27, 28], and such response was recorded also in postmenopausal women only after hormonal replacement therapy [29]. All these reports sustain the fact that estrogens modulate the opioidergic blockade and when naltrexone cloridrate is administered in FHA, LH plasma levels start to increase within few weeks [30]. In the last two decades, it has been demonstrated that also dopaminergic and serotoninergic pathways are deeply involved in the mechanisms that link stress-induced amenorrhea and reproductive function in FHA [24, 31, 32]. In addition, most of the patients that suffer really for a FHA show an elevation of the cortisol plasma levels close to the upper limits of normality, while in other amenorrheic conditions (i.e., hyperprolactinemic or hyperandrogenic amenorrhea) cortisol shows normal levels [33].

At the basis of the mechanism of stress, there is the perfect combination and overlapping of various independent situations that occur whenever the stressant condition(s) is long lasting or chronic. Psychological, metabolic, and physical stressors are the relevant ones that negatively impact on the brain and on the neurovegetative systems as well as on the neuroendocrine pathways. The central structure for the reproductive control is the hypothalamus where GnRH is synthetized and released. GnRH secretion is under a specific control of various other hypothalamic nuclei that are all around the paraventricular and sopraoptic nuclei where GnRH is secreted. These other nuclei control satiety, glucose, water, and salt levels, and they also receive inputs from the cortex and from other subcortical areas of the brain deeply connected on whatever refers to information coming from the environment in terms of sounds, sights, metabolism, and danger. Practically the hypothalamus is informed on whatever is going on inside and outside the human body. Whatever event changes the perfect equilibrium of all these elements, it results to be able to activate a reaction by the hypothalamus so that to counteract such adverse environmental change and to predispose a defensive condition. Such hypothalamic activation parallel the occurrence of stressant situations, more frequent is the stress, more repetitive activation of the hypothalamic reaction leads to the significant changes that are observed under chronic stressant situations. The block that occurs on the reproductive axis is mainly exerted by the significant reduction of the amount of GnRH secreted by the hypothalamic nuclei (sopraoptic and paraventricular) that reduce the gonadotropin episodic discharge with the concomitant reduction of mean plasma concentrations of LH, FSH, and of ovarian steroids.

From what is described above, it appears evident that hypothalamus acts as a “computer” that takes care of all inputs and defines specific outputs to monitor/modulate/regulate a lot of other biological functions such as sleep, glucose control, heart function, feeding, reproduction, and many others. This happens also in males, but it is incredibly active and sensitive in females. Nowadays, weight control, physical activity, and a healthy choice of our food are primary elements of our everyday life. These are relevant issues since our western civilization is becoming even more overweight up to obese! Indeed, at least in Italy, progression of obesity has been up to 25 % in 25 years and the higher occurrence of obese-related diseases, such as diabetes, hypertension, stroke, has stimulated a part of the population to keep weight and feeding under control. Within this last decade, a higher amount of women started to exercise more than 20 years ago and a certain percentage of them realized that they could move from simple physical activity to a more serious training. It is clear that physical activity is absolutely a healthy element in our everyday life, but the excess of training can frequently occur and this can induce negative effects of the reproductive ability of young girls as well of adult women [34]. These negative effects have been identified in a lower fertility rate due to a higher anovulatory condition. Moreover, it is relevant to note that the pregnancy rate of patients that attend IVF programs are incredibly lower for those women that train too much or have an agonistic training [35–37] and that the more is the training the higher is the infertility risk (3.2 fold than controls) [37].