It is widely known that estrogen has a fundamental role to play in skeletal homeostasis. In the most reductionist sense, the action of estrogen can be surmised as anti-resorptive. Estrogen prevents the break-down of bone. It therefore follows that estrogen deficiency states, such as the menopause and functional hypothalamic amenorrhoea (FHA), are often characterised by increased bone remodelling and disrupted skeletal homeostasis. FHA is the cessation of menstruation secondary to abnormal signalling between the hypothalamus and pituitary gland due to deficient pulsatile secretion of Gonadotrophin Releasing Hormone (GnRH). Functional hypothalamic amenorrhoea is frequently a consequence of women suffering with eating disorders. The development of FHA secondary to eating disorders is an evolutionary adaptive response to chronic metabolic energy deficiency. Fundamentally, preservation of life is biologically prioritised over dispensable physiological process such as reproduction. Consequently, the hypothalamic-pituitary-ovarian (HPO) axis fails, which disrupts menstrual function and ovulation, culminating in a state of estrogen deficiency. One of the most important and long-lasting deleterious consequences of FHA is disrupted skeletal homeostasis and bone loss. Estrogen replacement, most commonly in the form of combined hormone replacement therapy (HRT) or the combined oral contraceptive pill (COCP), is advised for women with an early menopause to prevent bone loss. Arguably, estrogen replacement should also be utilised in the context of FHA. However, the optimum estrogen regime for women with FHA remains under-researched and so management is not evidence-based.

Reproductive conditions secondary to disorders of the hypothalamic-pituitary-gonadal (HPG) axis are common and are associated with important health implications and considerable psychosocial impact. Basal and dynamic tests enable interrogation of individual components of the HPG axis, facilitating diagnosis and understanding of the pathophysiology of reproductive disorders. Onset of puberty is controlled by hypothalamic gonadotrophin-releasing hormone (GnRH) neuronal function. To date, a dynamic test of hypothalamic function is not yet available. Therefore, accurate differentiation of pubertal disorders such as constitutional delay of growth and puberty (CDGP) and congenital hypogonadotrophic hypogonadism (CHH) as causes of delayed puberty is challenging due to similar clinical presentations and hormonal profiles. Likewise, although the two commonest reproductive disorders in women, polycystic ovary syndrome (PCOS) and functional hypothalamic amenorrhoea (FHA) have disparate hypothalamic function, oligo/amenorrhoea frequently poses a diagnostic conundrum owing to the overlap in the criteria used to define both conditions. This review aims to describe pubertal and reproductive disorders secondary to pathologies affecting the HPG axis. Challenges encountered in clinical practice in differentiating pubertal and reproductive conditions are reviewed in conjunction with the utility of baseline and dynamic endocrine tests to interrogate specific components of the HPG axis. We also highlight putative hypothalamic, pituitary, and gonadal markers in development that could improve the diagnosis of patients presenting with disorders of puberty or reproduction.

The aim of the study was to investigate whether serum Luteinizing Hormone (LH) levels in women with Functional Hypothalamic Amenorrhoea (FHA) and Polycystic Ovarian Morphology (PCOM) are still associated to Body Mass Index (BMI) and/or serum insulin and/or Anti-Müllerian Hormone (AMH) levels using a larger population of FHA.
Retrospective observational study (2006-2020).
Data from 62 FHA patients were used for this study using strict criteria to define them.
Serum LH, FSH, 17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone sulphate (DHEA-S), androstenedione, total testosterone, prolactin, Sex Hormone Binding Globulin (SHBG) and AMH levels were measured by immunoassay. To homogenize the AMH values, we converted those obtained after 2015. We defined PCOM with strict criteria: a follicle number per ovary (FNPO) ≥12 or ≥20 per ovary, depending on the date on which the assessment was carried out and the ultrasound device.
Forty-two percentage of our FHA population had PCOM. The PCOM+ group had significantly higher ranks of BMI (p = .024) and serum AMH levels (p = .0001) and significantly lower ranks of serum FSH levels (p = .002). LH was positively correlated with fasting insulin (p = .011) and with AMH (p = .035) in the PCOM+ group only but not with BMI. There was a positive correlation between LH and FSH in both groups.
Our study suggests that GnRH insufficiency in women with PCOM unravels some mechanisms of LH regulation that are poorly documented in the literature and may involve a direct pituitary effect, as suggested by our results with serum insulin and AMH levels.

One of the most important and potentially long-lasting detrimental consequences of Functional Hypothalamic Amenorrhoea (FHA) is on skeletal homeostasis. Beyond oestrogen deficiency, FHA is associated with a cascade of additional neuro-endocrine and metabolic alterations, some adaptive, but which combine to disrupt skeletal homeostasis. Ultimately, this leads to a two-fold increased risk of fractures in women with FHA compared to healthy eumenorrhoeic women. Although the cornerstone of management of FHA-related bone loss remains recovery of menses via restoration of metabolic/psychological balance, there is rapidly developing evidence for hormonal manipulations (with a particular emphasis on route of administration) and other pharmacological treatments that can protect or improve skeletal homeostasis in FHA. In this mini-review, we provide an update on the pathophysiology, clinical management and future avenues in the field from a bone perspective.

Secondary oligo/amenorrhoea occurs in 3%-5% of women of reproductive age. The two most common causes are polycystic ovary syndrome (PCOS) (2%-13%) and functional hypothalamic amenorrhoea (FHA) (1%-2%). Whilst both conditions have distinct pathophysiology and their diagnosis is supported by guidelines, in practice, differentiating these two common causes of menstrual disturbance is challenging. Moreover, both diagnoses are qualified by the need to first exclude other causes of menstrual disturbance.
To review clinical, biochemical and radiological parameters that could aid the clinician in distinguishing PCOS and FHA as a cause of menstrual disturbance.
FHA is uncommon in women with BMI > 24 kg/m2 , whereas both PCOS and FHA can occur in women with lower BMIs. AMH levels are markedly elevated in PCOS; however, milder increases may also be observed in FHA. Likewise, polycystic ovarian morphology (PCOM) is more frequently observed in FHA than in healthy women. Features that are differentially altered between PCOS and FHA include LH, androgen, insulin, AMH and SHBG levels, endometrial thickness and cortisol response to CRH. Other promising diagnostic tests with the potential to distinguish these two conditions pending further study include assessment of 5-alpha-reductase activity, leptin, INSL3, kisspeptin and inhibin B levels.
Further data directly comparing the discriminatory potential of these markers to differentiate PCOS and FHA in women with secondary amenorrhoea would be of value in defining an objective probability for PCOS or FHA diagnosis.

Functional hypothalamic amenorrhoea (FHA) can occur due to the independent or combined effects of psychogenic and energetic stressors. In exercising women, research has primarily focused on energy deficiency as the cause of FHA while psychological stressors have been ignored. To assess both psychological and metabolic factors associated with FHA in exercising women, we performed across-sectional comparison of 61 exercising women (≥2 hours/week, age 18-35 years, BMI 16-25kg/m2), who were eumenorrheic or amenorrhoeic confirmed by daily urine samples assayed for reproductive hormone metabolites. Psychological factors and eating behaviours were assessed by self-report questionnaires. Exercising women with FHA had lower resting metabolic rate (p=0.023), T3 (p<0.001), T4 (p=0.013), leptin (p=0.002), higher peptide YY (p<0.001), greater drive for thinness (p=0.017), greater dietary cognitive restraint (p<0.001), and displayed dysfunctional attitudes, i.e., need for social approval (p=0.047) compared to eumenorrheic women. Amenorrhoeic women displayed asignificant positive correlation between the need for social approval and drive for thinness with indicators of stress, depression, and mood, which was not apparent in eumenorrheic women. In exercising women with FHA, eating behaviours are positively related to indicators of psychological stress and depression.

UNASSIGNED: To assess sleep disorders (SleD) in women with functional hypothalamic amenorrhoea (FHA) and to identify possible associations with known FHA predisposing factors.
UNASSIGNED: We conducted a prospective case-control study spanning the period January 2016 to April 2018. We recruited forty-one FHA women and 86 healthy controls. We assessed SleD and other FHA predisposing factors via self-reported questionnaires. The Spearman\'s correlation coefficient (rho) was used to examine possible correlations among the different variables. Multivariate logistic regression analysis was conducted to identify independent factors associated with SleD.
UNASSIGNED: Women with FHA reported having higher SleD (p = 0.004), abnormal eating attitudes (p < 0.0001), higher anxiety levels (AL) (p < 0.0001), overweight preoccupation (P < 0.0001) and increased weekly physical activity (p = 0.004). There was a significant positive correlation between SleD and AL (rho = 0.88, p < 0.0001). Significant correlation was also found between AL and several Athens insomnia scale constituents, including sleep induction (rho = 0.53, p = 0.0004), awakenings during the night (rho = 0.6, p < 0.0001), final awakening (rho = 0.42, p = 0.006), total sleep duration (rho = 0.64, p < 0.0001), quality of sleep (rho = 0.63, p < 0.0001), well-being during the day (rho = 0.34, p = 0.03) and sleepiness during the day (rho = 0.51, p = 0.007). High AL were correlated with 2.83-fold increased SleD risk (p = 0.04).
UNASSIGNED: FHA women are seemingly more prone to SleD and those with SleD suffer from higher AL. In view of this evidence, the potential rationale of adding psychological and SleD evaluation to their clinical care is highlighted.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is a heterogeneous disorder with clinical features shared with functional hypogonadotrophic hypogonadism (FHH).
OBJECTIVE: To investigate the usefulness of an elevated (>40 pmol/L) anti-Mullerian hormone (AMH) in identifying PCOS and distinguishing PCOS from FHH.
METHODS: 141 patients with an elevated AMH and body mass index either <20 kg/m2 (lean) or >30 kg/m2 (obese) were selected and three subgroups analysed - obese, lean, lean with suspected FHH. FHH was diagnosed clinically, incorporating diet, weight and exercise history; confirmatory tests included pituitary MRIs, progestin challenges and endometrial thickness measurements. PCOS features of oligo/anovulation, polycystic ovarian morphology (PCOm) and hyperandrogenism were determined by clinical history, pelvic ultrasound, free androgen index and physical examination, respectively. Features of PCOS and blood levels of AMH, follicle-stimulating hormone, luteinising hormone, sex hormone binding globulin (SHBG) and testosterone were compared between subgroups.
RESULTS: Of 141 patients with elevated AMH, 76 were obese and 65 lean. Greater than one-third of lean women had the clinical picture of FHH. Elevated AMH predicted PCOm and menstrual irregularity across all subgroups but uniquely associated with hyperandrogenism in the obese. Median AMH levels were similar among FHH and non-FHH women. Median SHBG levels were significantly higher (111 ± 73 vs 56 ± 31, P < 0.001) in lean women with FHH compared to those without FHH.
CONCLUSIONS: PCOS and FHH share common features of elevated AMH levels, oligo-anovulation and polycystic ovarian morphology. AMH did not assist in differentiating FHH from PCOS. A higher SHBG level shows promise as a discriminatory finding in FHH.

Functional hypothalamic amenorrhoea (FHA) is a neuroendocrine disorder caused by an energy deficit and characterized by low leptin levels. Based on this, previous studies have suggested that leptin administration may play a crucial role in FHA treatment. However, FHA is also associated with abnormal psychosocial and dietary behaviour that needs to be addressed. In this context, this systematic review examined the efficacy of leptin treatment, non-pharmacological therapy and nutritional interventions in FHA. PubMed, Medline and Cochrane Library databases were searched in order to find relevant papers, including randomized controlled trials, clinical trials, prospective studies and case reports. The effects of different treatments on reproductive function, hormonal status and bone markers were recorded. Studies regarding other forms of treatment were excluded. In total, 111 papers were retrieved. After the removal of 29 duplicate papers, the abstracts and titles of 82 papers were examined. Subsequently, 53 papers were excluded based on title, and seven papers were omitted based on abstract. The remaining 11 papers were used: three based on leptin treatment, three regarding non-pharmacological treatment and five regarding dietary intervention. This literature review indicates that all of these treatment strategies improved reproductive function and hormonal status significantly, although conclusive results could not be drawn on bone markers. While leptin may be a promising new treatment, social aspects of FHA should also be addressed. As a result, a multifaceted therapeutic approach should be applied to treat affected women.