In a dangerous, acute situation the production of norepinephrine (also responsible for the feeling of fear) from locus coeruleus starts. In the same time, norepinephrine increases production of CRH with activation of hypothalamus–pituitary–adrenal axis and of sympathetic autonomous nervous system. The answer to stressing stimuli is mediated by β-endorphin, even if modulated by genetic variables. All physiological functions not fundamental for survival are restricted, as the ovarian function. The anatomic and functional proximity between GnRH-gonadotropin axis and CRH-ACTH axis allows rapid short inhibitory mechanisms on reproductive function in response to stress hormone hyperproduction. In a chronic stress state, the answer to chronic stimuli is modulated by feedback of rearrangement, acting through the same pathway of increased limbic–hypothalamic–pituitary–adrenal axis activity [9] and reduced central gonadotropin-releasing hormone (GnRH) drive [10–12].

Of note, stress and its resulting hormonal changes could trigger either undernutrition or overnutrition, depending on fuel availability, attitudes about food, and dietary behaviors such as bingeing, purging, overeating, or restricting. The answer to hormonal stress depends on age and weight, for this reason in adolescence it is stronger than in adults.

The energetic homeostasis is another crucial point to allow physiological reproductive function. Vagal nerve is the principal nervous input to central nervous system (CNS); this nerve is connected to gastric distension and cholecystokinin (CCK) and glucose production. Peripheral endocrine signals are various: leptin and adiponectin are signals produced by adipose tissue acting as feedback on hypothalamic nuclei regulating feeding and reproductive control. On the contrary, ghrelin, produced by cells of stomach fundus, is a short-term signal of energetic request. Both leptin and ghrelin play their role, respectively inhibitory and stimulating on appetite center, through arcuate nuclei, probably through pro-opiomelanocortin and the peptides derived from its cleavage. The feedbacks from other peripheral hormones produced by gastrointestinal tract are integrated at hypothalamic level: Peptide YY, GLP-1, Insulin, and Pancreatic polypeptide. These peripheral endocrine messages mix their information to hypothalamus with central afferences (as endocannabinoids and oxytocin).

The inhibitory effect of energetic deficit on hypothalamic function is a key point in menstrual dysfunctions of adolescent athletes, due to strenuous exercise sometimes associated to inadequate energy intake. This can be expressed by inappropriate luteal phase, anovulatory cycles, oligomenorrhea, or secondary amenorrhea. It is important to keep in mind that the same endocrine system that binds energetic restriction and menstrual alteration produces effects on bone turnover, increasing reabsorption and reducing neoformation in the adolescent age, causing a problem in reaching or maintaining peak bone mass.

Amenorrhea, low bone density, and eating disorders, the so-called “Athletic Triade,” expose these girls to high risk of stress fractures. Stress fractures are normally not due a single traumatic event, but to multiple bone stresses. The bones most frequently interested are tibia, metatarsi, and navicular, due to their particular exposure to micro traumatic events.

Functional hypothalamic amenorrhea is a diagnosis established after exclusion of other conditions having similar manifestation. The diagnostic workup should be based on the history of menstrual disorders. In the majority of cases normal menses with ovulatory cycles are followed by gradual loss of ovulation, then the menses become rare till they completely disappear. A lack of menarche can also be the main manifestation of FHA in early pubertal girls (Chap. 2). A careful clinical history is essential for identifying these patients; familiar osteoporosis, low birth weight, bowel malabsorption, previous fractures, late menarche, and low sun exposition are also important factors for bone mineral density deficiency; the number of hours of physical activity per day or week, eating diary, and menstrual diaries are also useful. Family conflicts, problems with the peers, school difficulties, and stressful events should also be investigated. The measure of height and weight and body mass index (BMI) is fundamental. DXA (Dual energy X-ray Absorption) and BIA (Bioelectrical Impedance Assessment) are useful tools to assess body composition. The impedance assessment is based on low frequency electric energy modifications passing through the body. The attenuation (resistance) is mainly due to the presence of water, which is mainly related to muscle mass. This exam primarily evaluates hydration and nutritional state. Generally, a good hydration should be around 60% and lean mass 78–80%. The measure of fat mass is indirect and for this reason is not totally reliable. Athletic girls often present reduced levels of intracellular water due to thermoregulation induced by physical effort. The body cellular mass (BCM) expresses the metabolically active part of the body: a cutoff level of 7 is considered expression of undernutrition. The DXA total body is a more precise mean of studying body composition, even if it is expensive and minimally radiant. It consents the evaluation of Bone Mineral Density (BMD) using references for age. Ultrasound pelvic is a useful complementary examination because endometrial thickness is an indirect measure of estradiol levels. Ovary echo-structures can be extremely various: multi-follicular or micro-follicular with low vascularization to color Doppler (Table 7.4).

We can use progesterone challenge test to check the endometrial estrogenization [13]; performing the test blood sampling for hormonal profile can take place during bleeding. In the past medroxyprogesterone acetate 10 mg for 10 days has been extensively used: menstrual bleeding could be expected with an endometrial thickness >6 mm. Nowadays micronized progesterone 100 mg/day twice/day for 10 days is preferred, but it doesn’t exist yet a definition of endometrial thickness related to the bleeding answer.

Treatment of menstrual disorders, and secondary amenorrhea resulting from hypothalamic disorders should be aimed at the elimination of the primary cause, i.e., a decrease in psycho-emotional strain, avoidance of chronic stressors, reduction of physical exercise level, or optimization of BMI in patients who lose weight [14].

A cognitive-behavioral therapy can be proposed to help coping with stress response or modifying habits related to diet and physical exercise, working on body image difficulties or problem-solving skills. A reduction of stress response and the restoration of metabolic equilibrium is the main street to resume normal menses and ovulation. Usually, menstrual function resumes spontaneously as a result of lifestyle modification or of environmental changes (e.g., changing school).

If menses do not resume after a period of 6 months or primary causative treatment is not possible, e.g., in competitive athletes or ballet dancers, neutralization of hypoestrogenism consequences especially unfavorable effects on bone metabolism becomes the main issue. Hormonal preparations should be introduced into therapeutic protocol on an individualized basis; the patient’s expectations with regard to treatment outcomes should also be considered. In situations with long-lasting low energy intake, the bone sparing effect of estroprogestins is probably ineffective.