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including Psychoneuroimmunology, Neuro
Reproductive Medicine, Chronobiology
and Human Ethology
ISSN 0172–780X

NEL Vol.23 No.4, August 2002

Melatonin production in hyperandrogenic women

2002; 23:315320
pii: NEL230402A04

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Cyproterone acetate-ethinyl estradiol treatment alters urinary 6-sulfatoxymelatonin excretion in hyperandrogenic women
Rafael Luboshitzky 1,2, Paula Herer 2 & Zila Shen-Orr 3

1. Endocrine Institute, Haemek Medical Center, Afula, Israel.
2. B.Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.
3. Endocrine Laboratory, Rambam Medical Center, Haifa, Israel.

Key words:
melatonin; hyperandrogenism; cyproterone acetate; estradiol; androgens; adrenal hyperplasia and idiopathic hirsutism

Submitted: May 24, 2002
Accepted: May 25, 2002


OBJECTIVES: To investigate melatonin production in hyperandrogenic women before and during treatment with cyproterone acetate and ethinyl estradiol (Diane 35).

MATERIAL AND METHODS: We studied 10 women with late onset adrenal hyperplasia due to 21-hydroxylase deficiency (LOCAH) and 10 women with idiopathic hirsutism (IH). Patients were treated with Diane 35 for four months. Fasting blood samples for the determination of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone and dihydroepiandrosterone sulfate (DHEAS) and 24-hour urine collections for the determination of 6-sulfatoxymelatonin (aMT6s) excretion were obtained from all patients at baseline and after 4 months of treatment. Results were compared with those obtained in 15 control women.

RESULTS: At baseline, women with LOCAH had significantly higher serum testosterone, 17-hydroxyprogesterone (17OHP) and ACTH stimulated 17OHP values than IH and control women. Their aMT6s values (51.0±20.5 mg/24h) were significantly higher than the values in IH (34.3±7.1) and control women (30.5±6.5) (p< 0.001). Diane 35 treatment significantly decreased serum LH, FSH and testosterone levels and aMT6s values in LOCAH patients (29.8±16.6 mg/24h) (p<0.0001) in LOCAH patients.

CONCLUSIONS: These results indicate that hyperandrogenic women with LOCAH have increased melatonin production. The normalization of aMT6s and testosterone values during cyproterone acetate-ethinyl estradiol treatment, suggest that sex steroids either directly or through the suppression of gonadotropin, modulate melatonin secretion in these patients.

1. ACTH Adrenocorticotropic hormone
2. aMT6s 6-sulfatoxymelatonin
3. BMI Body mass index
4. DHEAS dihydroepiandrosterone sulfate
5. DIANE 35 cyproterone acetate-ethinyl estradiol
6. FSH follicle-stimulating hormone
7. IH idiopathic hirsutism
8. LH luteinizing hormone
9. LOCAH late onset adrenal hyperplasia due to 21-hydroxylase deficiency
10. 17OHP 17-hydroxyprogesterone


The role of melatonin in human reproduction is still enigmatic at present. A large body of information suggests that melatonin and the reproductive hormones are inter-related under both physiological and pathological conditions [1]. This concept is based on observations of increased melatonin levels in hypogonadal patients with GnRH deficiency [2–5], decreased melatonin concentrations in precocious puberty [6] and in primary hypogonadism [7–8]. Testosterone or estradiol (E2) replacement therapy given to hypogonadal patients normalized their melatonin levels [3–4,8]. Long-term melatonin administration given to men decreased sperm density and motility as well as seminal plasma E2 levels [9].
Melatonin secretion profiles in hyperandrogenic women were examined in only few studies. In children with congenital adrenal hyperplasia, plasma melatonin levels were normal and replacement therapy with glucocorticoids did not modify their melatonin levels [10]. In hyperandrogenic non-obese women, urinary sulfatoxymelatonin concentrations were higher compared to matched controls [11]. Recently, we have demonstrated that women with late onset adrenal hyperplasia due to 21-hydroxylase deficiency (LOCAH) had elevated melatonin production that was associated with their increased androgen levels [12]. Compared with LOCAH, idiopathic hirsutism (IH), a form of hyperandrogenism found in women with regular ovulatory cycles and normal androgen levels, results from hyperactivity of 5a-reductase in peripheral tissue [13]. Cyproterone acetate is the most widely used drug for the treatment of hirsutism [14]. Treatment of polycystic ovary syndrome and idiopathic hirsutism patients with cyproterone acetate-ethinyl estradiol (Diane 35) effectively decreased the hirsutism score and reduced androgen levels in these patients [15–16].
The measurement of urinary 6-sulfatoxymelatonin (aMT6s), the major metabolite of melatonin, was shown to correlate with plasma hormone levels and is considered to be a good indicator of pineal melatonin secretion [17–19].
To further delineate possible relations between melatonin and the reproductive hormones, we studied melatonin secretion, as determined by the 24-hour urinary aMT6s excretion, in hyperandrogenic women with LOCAH and IH before and after 4 months of antiandrogen treatment with Diane 35.

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