Recovery of menses after functional hypothalamic amenorrhoea: if, when and why

Abstract

BACKGROUND Prolonged amenorrhoea occurs as a consequence of functional hypothalamic amenorrhoea (FHA) which is most often induced by weight loss, vigorous exercise or emotional stress. Unfortunately, removal of these triggers does not always result in the return of menses. The prevalence and conditions underlying the timing of return of menses vary strongly and some women report amenorrhoea several years after having achieved and maintained normal weight and/or energy balance. A better understanding of these factors would also allow improved counselling in the context of infertility. Although BMI, percentage body fat and hormonal parameters are known to be involved in the initiation of the menstrual cycle, their role in the physiology of return of menses is currently poorly understood. We summarise here the current knowledge on the epidemiology and physiology of return of menses. OBJECTIVE AND RATIONALE The aim of this review was to provide an overview of (i) factors determining the recovery of menses and its timing, (ii) how such factors may exert their physiological effects and (iii) whether there are useful therapeutic options to induce recovery. SEARCH METHODS We searched articles published in English, French or German language containing keywords related to return of menses after FHA published in PubMed between 1966 and February 2020. Manuscripts reporting data on either the epidemiology or the physiology of recovery of menses were included and bibliographies were reviewed for further relevant literature. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria served to assess quality of observational studies. OUTCOMES Few studies investigate return of menses and most of them have serious qualitative and methodological limitations. These include (i) the lack of precise definitions for FHA or resumption of menses, (ii) the use of short observation periods with unsatisfactory descriptions and (iii) the inclusion of poorly characterised small study groups. The comparison of studies is further hampered by very inhomogeneous study designs. Consequently, the exact prevalence of resumption of menses after FHA is unknown. Also, the timepoint of return of menses varies strongly and reliable prediction models are lacking. While weight, body fat and energy availability are associated with the return of menses, psychological factors also have a strong impact on the menstrual cycle and on behaviour known to increase the risk of FHA. Drug therapies with metreleptin or naltrexone might represent further opportunities to increase the chances of return of menses, but these require further evaluation. WIDER IMPLICATIONS Although knowledge on the physiology of return of menses is presently rudimentary, the available data indicate the importance of BMI/weight (gain), energy balance and mental health. The physiological processes and genetics underlying the impact of these factors on the return of menses require further research. Larger prospective studies are necessary to identify clinical parameters for accurate prediction of return of menses as well as reliable therapeutic options.

Clinical and biochemical discriminants between functional hypothalamic amenorrhoea (FHA) and polycystic ovary syndrome (PCOS)

“…4 Although the set point for body weight at which menses are lost varies between individuals (generally BMI < 24 kg/m 2 , Table 1), intriguingly recovery of menses may require ~2 kg more than this set point and take up to 2 years after regain of normal body weight. 18 Recovery of menstrual function was observed in 86% of adolescents with AN who reached ≥90% of their ideal body weight, 19 and in 78% of women with FHA who gained weight (BMI 22 kg/m 2 in recovered vs 20 kg/ m 2 in unrecovered). 20 In summary, FHA is uncommon in overweight women, whereas both PCOS and FHA can occur in women with low/normal BMI's (Figure 1).…”

“…Furthermore, one third of athletes had amenorrhoea despite ‘normal’ BMI (21.3 ± 1.6 kg/m 2 ), 17 whereas two thirds of women with AN had amenorrhoea at a BMI between 17 and 18.9 kg/m 2 4 . Although the set point for body weight at which menses are lost varies between individuals (generally BMI < 24 kg/m 2 , Table 1), intriguingly recovery of menses may require ~2 kg more than this set point and take up to 2 years after regain of normal body weight 18 . Recovery of menstrual function was observed in 86% of adolescents with AN who reached ≥90% of their ideal body weight, 19 and in 78% of women with FHA who gained weight (BMI 22 kg/m 2 in recovered vs 20 kg/m 2 in unrecovered) 20 …”

Basal and dynamic relationships between serum anti-Müllerian hormone and gonadotropins in patients with functional hypothalamic amenorrhea, with or without polycystic ovarian morphology

“…Functional hypothalamic amenorrhea (FHA) is considered to be due to chronic anovulation without identifiable organic causes [ 1 ]. It has its direct origin in a functional decrease or stop of pulsatile Gonadotropin Releasing Hormone (GnRH) secretion, which results in insufficient ovarian function [ 1 ] and is thought to be restorable when causative behavioural factors are corrected [ 2 , 3 ]. In a very recent study on FHA and controls, Makollé et al demonstrated that the serum levels of anti-Mullerian hormone (AMH) were significantly lower in FHA patients without polycystic ovarian morphology (PCOM) than in controls [ 4 ].…”

“…The GnRH stimulation test has been considered a useful tool in the diagnosis of FHA [ 13 ]. Of note, despite the miscellaneous definitions of FHA which have been used in clinical studies, the GnRH stimulation test has been used only rarely [ 3 ]. This is in line with recent recommendations [ 14 ].…”

Randomised controlled trial of the effects of increased energy intake on menstrual recovery in exercising women with menstrual disturbances: the ‘REFUEL’ study

“…At present, there is a lack of established definitions of 'menstrual recovery'. Investigators have used varying definitions (Pape et al, 2020), including the occurrence of a single menses (Kopp-Woodroffe et al, 1999;Cialdella-Kam et al, 2014), positive (Guebels et al, 2014), menses followed by two menstrual cycles <36 days in length (Lagowska et al, 2014), menstrual cycles <$36 days for at least 3 months (Arends et al, 2012), and at least three menses in a 6month time period (Misra et al, 2008). In non-exercising women with FHA, recovery has been defined as occurrence of spontaneous ovulatory menstrual cycle with/without pregnancy (Falsetti et al, 2002), or menses and evidence of ovulation with E 2 >100 pg/ml and progesterone >5 ng/ml (Berga et al, 2003), whereas partial recovery has been defined as E 2 >60 pg/ml and P 4 <5 ng/ml (Berga et al, 2003).…”