Hypogonadotrophic hypogonadism and primary amenorrhoea associated with increased melatonin secretion from a cystic pineal lesion

Abstract

A 17-year-old girl presented with primary amenorrhoea and failure to develop secondary sexual characteristics, although her height was above the 90th centile. Endocrine investigations revealed hypogonadotrophic hypogonadism (basal LH and FSH levels < 0.5 U/l; FSH rose to 2.0 U/l and LH to 1.0 U/l after GnRH). ACTH, GH, TSH and PRL secretion were normal. A magnetic resonance scan revealed no abnormality in the pituitary, pituitary stalk or hypothalamus but demonstrated a partly cystic enhancing lesion in the pineal region. Melatonin production (assessed as urinary 6-sulphatoxymelatonin: aMT6s) at baseline was markedly increased: 459-530 ng/kg/24 h compared with aged-matched controls: 136 +/- 69 (P = 0.01). However, melatonin production retained a largely normal rhythm with increased production during the night. Treatment with ethinyloestradiol 100 micrograms daily had no apparent effect on the production of melatonin. Treatment with atenolol, 100 mg daily at 1600 h, was associated with suppression of nocturnal melatonin secretion but a brisk rebound in the morning and a considerably delayed peak excretion time (10.2 h) compared with controls (3.9 h). It is likely the pineal lesion, which may be hyperplasia or possibly even tumour, was responsible for the increased melatonin secretion. These data support the hypothesis that melatonin may have a causal role in hypogonadotrophic hypogonadism.

Abnormal melatonin secretion in hypogonadal men: the effect of testosterone treatment

“…In the KS group, serum E 2 , FSH and LH levels were elevated prior to testosterone administration and remained so during treatment. Increased melatonin levels as observed in our IGD patients were also demonstrated in other studies (Puig-Domingo et al, 1992;Ozata et al, 1996;Walker et al, 1996). The effect of sex steroids on melatonin secretion was evaluated in several studies, both in male and female patients, but revealed conflicting results (Arendt et al, 1985;Puig-Domingo et al, 1992;Delfs et al, 1994;Bartsch et al, 1995;Commentz & Willing, 1995).…”

“…Functional melatonin receptors were demonstrated in human granulosa cell membranes (Yie et al, 1995), prostate (Gilad et al, 1996), hypothalamic suprachiasmatic nuclei and pituitary pars tuberalis (Weaver et al, 1993), suggesting that melatonin may act on the reproductive system at three sites. Abnormal melatonin secretion was demonstrated in women with hypothalamic amenorrhoea (Berga et al, 1988;Brzezinski et al, 1988), anorexia nervosa (Tortosa et al, 1989), secondary amenorrhoea (Okatani & Sagara, 1994), in patients with precocious puberty (Waldhauser et al, 1991), and in hypogonadotrophic hypogonadism (Puig-Domingo et al, 1992;Ozata et al, 1996, Walker et al, 1996.…”

Effect of propranolol plus exercise on melatonin and growth hormone levels in children with growth delay

“…The lack of sustained effects of b-adrenoceptor agonists on melatonin production could be due to the low doses of b-adrenoceptor agonists used. By contrast, propranolol and the b 1 -adrenergic antagonist atenolol produced a similar blocking effect on melatonin production in humans [Walker et al, 1996;Nathan et al, 1997]. These data, and those obtained in a recent study measuring the influence of specific b-blockade on melatonin production in humans, have revealed that b-blockers decrease melatonin release via specific inhibition of adrenergic b 1 -receptors [Stoschitzky et al, 1999].…”

“…In hypothalamic -pituitary dysfunction, the relationships between melatonin and GH are more apparent. Melatonin production increased in hypogonadotrophic hypogonadism, and treatment with atenolol was associated with suppression of nocturnal melatonin secretion but a brisk rebound in the morning and a considerably delayed peak excretion time [Walker et al, 1996]. Administration of propranolol decreased melatonin [Mayeda et al, 1998] and restored the gonadotropin response to gonadotropin-releasing hormone in anorexia [Pawlikowski and Zarzycki, 1999].…”

“…In normal subjects, melatonin displays a normal circadian rhythm under constant routine experiments without exercise, whereas GH secretion is modulated to some extent by circadian rhythms [Uchiyama et al, 1998]. Melatonin production increases in some situations involving hypothalamic -pituitary dysfunction [Walker et al, 1996;Pawlikowski and Zarzycki, 1999]. In acromegaly, parameters of the nocturnal melatonin peak (area under the curve, mesor and amplitude) were significantly lower than in the controls, with an earlier acrophase [Sinisi et al, 1997].…”