-  Histiocytosis X (Hans-Schüller-Christian disease) is characterized by multiple organ infiltration (skin, bone, viscera) by histiocytic cells. Infiltration of the pituitary stalk and hypothalamus is possible with diabetes insipidus and GH or gonadotropin deficiency. Enlargement of the pituitary stalk and diabetes insipidus are very suggestive; however, positive diagnosis requires histological analysis of the lesions that are easy to biopsy.

-  Sarcoid or tuberculous granuloma or secondary hemochromatosis may also but more rarely infiltrate the hypothalamo-pituitary axis and be associated with delayed puberty in girls.

-  Hydrocephalus may by compression caused by such a condition.

-  Traumatic, inflammatory, post-infectious or vascular lesions of the hypothalamo-pituitary axis are seldom responsible for such a condition.

Functional IHH
Any situation with a negative energetic balance may interfere with the pattern of LHRH pulsatile secretion through the leptin/NPY pathway or other neurotransmitters. Thus, quantitative and qualitative nutritional status, body mass index, body fat mass and plasma leptin levels are important features to assess in cases of severe systemic and chronic disease. A specific condition is characterized by a negative energetic balance related to a particular nutritional status.

Chronic Disorders
Many chronic diseases are associated with delayed or arrested pubertal development depending on the age of onset. Malnutrition, asthenia, negative energetic balance with reduced body mass index, body fat mass and/or qualitative nutritional deficiency may induce functional IHH by impairing pulsatile LHRH secretion. This must be distinguished from the primary effects of the disease.

• Digestive disease: celiac disease must be considered in cases of unexplained growth retardation and delayed puberty. Digestive manifestations may be absent. Positive diagnosis is made by detection of specific antitransglutaminase antibodies and the typical aspect with atrophic villosities seen on jejunal biopsies.
• Inflammatory bowel diseases may also be associated with delayed puberty in cases of weight loss and steroid treatment.
• Chronic pulmonary disease such as cystic fibrosis can induce the same deficiency in large part due to malnutrition.
• Chronic renal disease before transplantation or steroid-sensitive nephrotic syndrome.
• Major thalassemia or sickle cell disease can impair sexual maturation in the same way or by iron deposition in the pituitary gland.

Negative Energetic Balance
Undernutrition of any origin, intentional or not, delays puberty in girls.
The secular trend toward earlier onset of puberty in girls is consecutive to the generally improved nutrition in developed countries. Food restriction, vegetarian diets, and disturbed food behavior as in anorexia nervosa can be associated with delayed puberty and/or primary or secondary amenorrhea.

Anorexia Nervosa is a severe disease with distorted body image, food avoidance, severe weight loss with hyperactivity, decreased basal metabolic rate, hypothermia, constipation, bradycardia and hypotension and severe metabolic abnormalities leading sometimes to death. Leptin is very low in relation to weight loss and lack of body fat mass while the gonadal axis remains at or returns to an infantile state.

Intensive exercise in young girls (ballet dancers, athletes, gymnasts) may be associated with delayed puberty due to a negative energetic balance, special diet, and stimulation of the corticotropic axis (endorphins, ACTH, cortisol) under exaggerated stress, leading to impaired pulsatile LHRH secretion.