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Objective: To investigate whether allopregnanolone, a neuroactive steroid involved in modulating behavioural and neuroendocrine functions, shows episodic secretion in eumenorrheic women, during the follicular and luteal phases of the menstrual cycle, and in women with stress-induced amenorrhea. Patients: Six eumenorrheic women and 14 women with hypothalamic amenorrhea were enrolled for the present study. Methods: All subjects underwent hormonal evaluation in baseline conditions and a pulsatility study to determine LH, cortisol and allopregnanolone episodic release. Eumenorrheic subjects were investigated twice, in the follicular phase (days 3-7) and in the luteal phase (days 18-22) of the menstrual cycle. LH, FSH, prolactin, estradiol, phosphate, DHEA, allopregnanolone and cortisol levels were evaluated in each case. Results: In healthy women, serum gonadotropin and gonadal steroid levels were significantly lower (P , 0:01 and P , 0:05 respectively) than those in amenorrheic subjects. Allopregnanolone was higher in amenorrheic subjects and during the luteal phase, compared with the follicular phase, of eumenorrheic subjects ðP , 0:01Þ: Pulse analysis revealed a significant episodic discharge of allopregnanolone in all subjects (follicular phase 6:5^0:3 peaks/6 h and luteal phase 5:5^0:4 peaks/6 h, hypothalamic amenorrhea 7:0^0:7 peaks/6 h) with higher pulse amplitude in amenorrheic subjects and during the luteal phase compared with the follicular phase of the eumenorrheic subjects ðP , 0:05Þ: Moreover, the specific concordance index demonstrated that allopregnanolone is coupled with LH only during the luteal phase of the cycle and with cortisol during both phases. Allopregnanolone -cortisol coupling was also observed in amenorrheic subjects. Conclusions: Allopregnanolone is secreted episodically. Both the ovary and adrenal glands release this steroid hormone and it shows temporal coupling with LH only during the luteal phase, with cortisol during both the studied phases of the menstrual cycle in eumenorrheic women and again with cortisol in hypothalamic amenorrheic patients.

Our data demonstrate that metformin administration modulates LH secretion as well as cortisol and allopregnanolone pulsatile release. In addition, the results demonstrate that adrenal and ovarian steroidogenic activity is greatly modulated by any change in insulin sensitivity.

Hypothalamic amenorrhea (HA) is a secondary amenorrhea with no evidence of endocrine/systemic causal factors, mainly related to various stressors affecting neuroendocrine control of the reproductive axis. In clinical practice, HA is mainly associated with metabolic, physical, or psychological stress. Stress is the adaptive response of our body through all its homeostatic systems, to external and/or internal stimuli that activate specific and nonspecific physiological pathways. HA occurs generally after severe stress conditions/situations such as dieting, heavy training, or intense emotional events, all situations that can induce amenorrhea with or without body weight loss and HA is a secondary amenorrhea with a diagnosis of exclusion. In fact, the diagnosis is essentially based on a good anamnestic investigation. It has to be investigated using the clinical history of the patient: occurrence of menarche, menstrual cyclicity, time and modality of amenorrhea, and it has to be exclude any endocrine disease or any metabolic (i.e., diabetes) and systemic disorders. It is necessary to identify any stress situation induced by loss, family or working problems, weight loss or eating disorders, or physical training or agonist activity. Peculiar, though not specific, endocrine investigations might be proposed but no absolute parameter can be proposed since HA is greatly dependent from individual response to stressors and/or the adaptive response to stress. This article tries to give insights into diagnosis and putative therapeutic strategies.

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