Functional Hypothalamic Amenorrhea Seen From Different Perspectives

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Mini Review
11 October 2022

In the original definition by Klinefelter, Albright and Griswold, the expression “hypothalamic hypoestrogenism” was used to describe functional hypothalamic amenorrhoea (FHA). Given the well-known effects of estrogens on bone, the physiopathology of skeletal fragility in this condition may appear self-explanatory. Actually, a growing body of evidence has clarified that estrogens are only part of the story. FHA occurs in eating disorders, overtraining, and during psychological or physical stress. Despite some specific characteristics which differentiate these conditions, relative energy deficiency is a common trigger that initiates the metabolic and endocrine derangements contributing to bone loss. Conversely, data on the impact of amenorrhoea on bone density or microarchitecture are controversial, and reduced bone mass is observed even in patients with preserved menstrual cycle. Consistently, oral estrogen-progestin combinations have not proven beneficial on bone density of amenorrheic women. Low bone density is a highly prevalent finding in these patients and entails an increased risk of stress or fragility fractures, and failure to achieve peak bone mass and target height in young girls. Pharmacological treatments have been studied, including androgens, insulin-like growth factor-1, bisphosphonates, denosumab, teriparatide, leptin, but none of them is currently approved for use in FHA. A timely screening for bone complications and a multidisciplinary, customized approach aiming to restore energy balance, ensure adequate protein, calcium and vitamin D intake, and reverse the detrimental metabolic-endocrine changes typical of this condition, should be the preferred approach until further studies are available.

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Review
11 August 2022
Epigenetics of functional hypothalamic amenorrhea
L. Fontana
3 more and 
M. Miozzo

Functional hypothalamic amenorrhea (FHA) is a temporary infertility characterized by the suppression of the hypothalamic–pituitary–gonadal (HPG) axis, induced by the inhibition of the hypothalamic pulsatile secretion of the gonadotropin-releasing hormone (GnRH), in the presence of stressors, including eating disorders, excessive exercise, and psychological distress. Although the stressful factors that may lead to FHA are well-established, little is known about the inter-individual variability in response to stress and the consequent inhibition of the HPG axis. Not all women, indeed, manifest FHA in presence of stressful conditions. Recent studies highlighted a genetic contribution to FHA. Rare or polymorphic variants in genes that control the development and/or function of GnRH neurons may contribute, indeed, to the adaptability of the reproductive axis to stress factors. Also epigenetic changes have been associated with different pathways involved in the HPG axis and therefore, take part in FHA and confer a personal predisposition to anovulation consequent to a stressful event, or represent biological markers of response to stress. This review summarizes recent advances in the identification of the contribution of (epi)genetics to FHA and to long-term complications of functional amenorrhea, and reports insights into the involvement of additional genetic loci in FHA development on the bases of the clinical and molecular overlap with other gynecological and/or psychological conditions. Finally, we describe the promising application of induced pluripotent stem cells (iPSCs) as a new approach to investigate the molecular pathways involved in FHA.

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The expression of Kisspeptin was detected by immunofluorescence. Blue represents DAPI nuclear staining, and red represents Kisspeptin immunofluorescence staining. control: control group, stress: restraint stress group. 3V, Third ventricle. n=3.
Original Research
24 May 2022

Background: Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, affecting energy homeostasis and reproduction. The aim of this study was to investigate whether stress affected energy metabolism and reproduction through the glucocorticoid receptor on Kisspeptin neurons in the hypothalamus.

Methods: Four groups included control group, chronic restraint stress group, Kisspeptin specific glucocorticoid receptor knock out group (KGRKO) and KGRKO+stress group. Body weight, food intake, estrous cycle of female mice, serum sex hormone levels, serum corticosterone and prolactin, Kisspeptin expression in the hypothalamus were measured.

Results: The restraint stress group showed a significant weight loss compared with the control group. KGRKO+restraint stress group had a reduced weight loss, suggesting that restraint stress might partially affect the energy metabolism through GR on Kisspeptin neurons. In terms of reproductive function, the restraint stress group and the KGRKO+restraint stress group showed missing pre-estrus period or prolonged estrous cycles. Serum LH and FSH in KGRKO + restraint stress group decreased significantly compared with KGRKO group. However, no significant difference in the level of serum testosterone was observed. After restraint stress, the levels of serum cortisol and prolactin in male and female mice were significantly higher than the control group, and the hypothalamus Kiss1 gene mRNA expression and Kisspeptin protein expression were significantly decreased.

Conclusion: Chronic restraint stress induced weight loss and negative changes in reproduction, which were partially mediated by glucocorticoid receptor on Kisspeptin neurons in the hypothalamus.

3,666 views
13 citations
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