Aetiology, previous menstrual function and patterns of neuro-endocrine disturbance as prognostic indicators in hypothalamic amenorrhoea

Human Reproduction Aetiology, previous menstrual function and patterns of neuro-endocrine disturbance as prognostic indicators in hypothalamic amenorrhoea Rebecca B.Perkins 0 Janet E.Hall 0 Kathryn A.Martin 0 0 Reproductive Endocrine Unit and National Center for Infertility Research, Massachusetts General Hospital , 55 Fruit Street BHX 5, Boston, MA 02114 , USA BACKGROUND: Hypothalamic amenorrhoea (HA) is a syndrome associated with infertility and osteopenia in reproductive-age women. METHODS: To understand better the natural history of this disorder, 28 women participated in a retrospective, questionnaire-based analysis to elucidate factors associated with spontaneous recovery. RESULTS: 54% of subjects developed HA related to an eating disorder, 21% related to stress weight loss, and 25% without obvious contributing factors (idiopathic). HA associated with a clear precipitant had a better prognosis than idiopathic HA (71 versus 29% recovery; P < 0.05). Reversal of the inciting factor appeared necessary but not sufficient for recovery (83% recovery if factor reversed). Normal menarche occurred in 61% of subjects, oligomenorrhoea in 32%, and primary amenorrhoea in 7%. Oligomenorrhoea and normal menarche showed a trend toward better prognosis than primary amenorrhoea (NS). Compared with controls, 46% of HA patients had decreased frequency of LH pulses, 7% decreased amplitude, 18% decreases in both frequency and amplitude, 18% absent pulses, and 11% normal-appearing pulses. Pulse pattern at baseline did not predict recovery. CONCLUSIONS: The aetiology of HA at the time of presentation predicts subsequent recovery of menstrual function. In stress, weight loss, or eating disorder-related HA, rates of recovery exceeded 80% when precipitating factors were reversed. Idiopathic HA may represent a different disorder as recovery rates were 30%. aetiology/hypothalamic amenorrhoea/neuro-endocrine/recovery - The clinical syndrome of hypothalamic amenorrhoea (HA) is characterized by amenorrhoea, hypo-oestrogenism, low or normal serum gonadotrophins, and a broad spectrum of abnormal patterns of hypothalamic gonadotrophin-releasing hormone (GnRH) secretion (Reame et al., 1985; Santoro et al., 1986; Perkins et al., 1999). HA accounts for 34% of secondary amenorrhoea (Reindollar et al., 1986), and is of clinical importance because the anovulation associated with HA precludes the possibility of achieving pregnancy without therapy (Martin et al., 1990) and the hypo-oestrogenic state associated with HA often results in osteopenia (Biller et al., 1991; Fabbri et al., 1991). HA has been associated with increased levels of exercise in female athletes (Feicht et al., 1978; Samuels et al., 1991; DeCree, 1998) regardless of percentage of body fat (Russell et al., 1984; Constantini and Warren, 1995). In non-exercising women, HA has been associated with weight loss (Nakamura et al., 1985; Kotsuji et al., 1993), even when women never dropped below the normal range of weight for height (Graham et al., 1979; Levine et al., 1994). Psychological stress has been cited as a causal factor in some cases (Hirvonen, 1977; Reindollar et al., 1986), and recent studies provide evidence for higher levels of dysfunctional attitudes, difficulty coping with stress (Giles and Berga, 1993), lower self-esteem, and a higher prevalence of psychological disturbances (Brown et al., 1983) in women with HA when compared with eumenorrhoeic controls and controls with amenorrhoea due to other causes. The association of amenorrhoea with anorexia nervosa is well established, and menstrual disturbances often begin prior to significant weight loss (Warren and van de Wiele, 1973; Fries, 1977; Falk and Halmi, 1982) and persist after recovery to normal weight (Golden et al., 1997; van Binsbergen et al., 1990; Garcia-Rubi et al., 1992). The ability of most women to retain normal menstrual cycles in the setting of stress, weight loss, or exercise suggests that women who develop HA have an underlying susceptibility to amenorrhoea. Previous studies indicate that menstrual patterns after menarche (referred to subsequently as primary menstrual function) might be linked to the development of HA later in life. One study of 262 patients with secondary amenorrhoea found menstrual irregularities prior to the onset of amenorrhoea in 1020% of patients who developed HA, but found no evidence of prior menstrual irregularities in women with amenorrhoea related to Cushings syndrome, hypothyroidism, Sheehans syndrome, pituitary tumours, or Ashermans syndrome (Reindollar et al., 1986). Other work indicates that athletes with prior menstrual irregularities are more susceptible to developing amenorrhoea than those with normal cycles at baseline (DeCree, 1998). Regardless of aetiology, HA is associated with a number of neuro-endocrine abnormalities involving the hypothalamic GnRH pulse generator. Some studies report a lower mean frequency of LH pulses in HA patients than in normally cycling women (Khoury et al., 1987; Berga et al., 1989), while previous work, including our own, has demonstrated a broader neuro-endocrine spectrum ranging from complete absence of LH pulsations to normal-appearing secretion patterns (Reame et al., 1985; Santoro et al., 1986; Perkins et al., 1999). Furthermore, LH secretion patterns often vary within an individual over time (Reame et al., 1985; Santoro et al., 1986; Perkins et al., 1999) in the absence of clinical change or menstrual resumption. Because the duration of amenorrhoea influences the likelihood that a patient will develop osteopenia (Biller et al., 1991), the probability of recovering menses spontaneously is central to issues of treatment. Large longitudinal follow-up studies of 90240 patients with HA related to weight loss have shown recovery rates ranging from 33% after 3 years (Nakamura et al., 1985) to 72% after 6 years (Hirvonen, 1977). Recovery of spontaneous menses following anorexia nervosa range from 56% after 6 years in an adult population (Hirvonen, 1977), to 68% after 1 year in an adolescent population (Golden et al., 1997). The only published follow-up of psychogenic and idiopathic HA cites 6 year recovery rates of 72 and 61% respectively (Hirvonen, 1977). Relationship of menstrual recovery to weight recovery in previous studies has been unclear due to relatively short follow-up and possible confounding psychological factors (Brown et al., 1983; Nakamura et al., 1985; Kotsuji et al., 1993). No study has yet explored the question of whether primary menstrual function or GnRH pulse patterns during amenorrhoea may predict subsequent recovery from HA. The design of the current study allowed intensive examination of factors affecting HA development and recovery in 28 patients, and addressed the following hypotheses: (i) women who develop HA in response to inciting factors have higher rates of recovery than women who develop HA in the absence of identifiable triggers, and this recovery is associate (...truncated)