Abstract
Evidence for a relationship between melatonin and the reproductive hormones in humans
is based on observations of abnormal melatonin secretion in clinical disorders of
the pituitary-gonadal axis. The aim of this study was to investigate melatonin production
in hyperandrogenic women before and during treatment with cyproterone acetate and
ethinyl estradiol (Diane 35). Twelve women with polycystic ovary syndrome (PCOS),
10 women with idiopathic hirsutism (IH), and 10 women with late onset adrenal hyperplasia
due to 21-hydroxylase deficiency (LOCAH) were studied. 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. At baseline,
women with PCOS and LOCAH had significantly higher testosterone and aMT6s values than
women with IH and controls. Diane 35 treatment significantly decreased testosterone,
LH, FSH and aMT6s values in PCOS and LOCAH patients compared with pretreatment values.
These results indicate that hyperandrogenic women with PCOS and LOCAH have increased
melatonin production. The decrease in aMT6s excretion together with reduced serum
LH, FSH, DHEAS and testosterone values during treatment with cyproterone acetate-ethinyl
estradiol, suggest that sex steroids either directly or through the suppression of
gonadotropins, modulate melatonin secretion in these patients.
Key words
Melatonin - cyproterone acetate - estradiol - androgens - polycystic ovary syndrome
References
- 1
Blaicher W, Imhof M H, Gruber D M, Schneberger C, Sator M O, Huber J C.
Endocrinological disorders focusing on melatonin interactions.
Gynecol Obstet Invest.
1999;
48
179-182
- 2
Bojkowski C J, Arendt J.
Factors influencing 6-sulphatoxymelatonin - a major melatonin metabolite in normal
human subjects.
Clin Endocrinol.
1990;
33
435-444
- 3
Brosen K.
Drug interactions and the cytochrome P450 system. The role of cytochrome P4501A2.
Clin Pharamacol.
1995;
29
20-25
- 4
Brzezinski A, Seibel M M, Lynch H J, Deng M H, Wurtman R J.
Melatonin in human preovulatory follicular fluid.
J Clin Endocrinol Metab.
1987;
64
865-867
- 5
Brzezinski A, Lynch H J, Seibel N M, Deng M H, Wurtman R J.
The circadian rhythm of plasma melatonin during the normal menstrual cycle and in
amenorrheic women.
J Clin Endocrinol Metab.
1988;
66
891-895
- 6
Caglayan S, Ozata M, Ozisik G, Turan M, Bolu F, Ontenli C, Arslan N, Erbil K, Gul D,
Ozdemir I C.
Plasma melatonin concentration before and during testosterone replacement in Klinefelter's
syndrome: Relation to hepatic indolamine metabolism and sympathoadrenal activity.
J Clin Endocrinol Metab.
2001;
86
738-743
- 7
Cardinali D P, Nagle C A, Rosner J M.
Control of estrogen and androgen receptors in the rat pineal gland by catecholamine
transmitter.
Life Sci.
1975;
16
93-106
- 8
Cardinali D P, Vacas M I, Keller-Sarmiento M I, Etchegogen G S, Pereyra E N, Chalayan H E.
Neuroendocrine integrative mechanisms in mammalian pineal gland: effect of steroid
and adenohypophyseal hormones on melatonin synthesis in vitro.
J Steroid Biochem.
1987;
27
565-571
- 9
Delfs T M, Baarks S, Fock C, Schumacher M, Olcese J, Zimmerman R C.
Sex steroids do not alter melatonin secretion in humans.
Hum Reprod.
1994;
9
49-54
- 10
Falsetti L, Gaubera A, Tisi G.
Efficacy of the combination ethinyl estradiol and cyproterone acetate on endocrine,
clinical and ultrasonographic profile in polycystic ovary syndrome.
Hum Reprod.
2001;
16
36-42
- 11
Fruzetti F, Bersi C, Parrini D, Ricci C, Genazzani A R.
Treatment of hirsutism: comparisons between different antiandrogen with central and
peripheral effects.
Fertil Steril.
1999;
71
445-451
- 12
Itoh M T, Ishizuka B, Kudo Y, Fusama S, Amemiya A, Sumi Y.
Detection of melatonin and serotonin N-acetyltransferase and hydroxyindole-O-methyltransferase
activities in rat ovary.
Mol Cell Endocrinol.
1997;
136
7-13
- 13
Kadva A, Djahanbakach O, Monson J, Di W L, Silman R.
Elevated nocturnal melatonin is a consequence of gonadotropin-releasing hormone deficiency
in women with hypothalamic ammenorrhea.
J Clin Endocrinol Metab.
1998;
83
3653-3662
- 14
Kovacs J, Brodner W, Kirchlechner V, Arif T, Waldhauser F.
Measurement of urinary melatonin: A useful tool for monitoring serum melatonin after
its administration.
J Clin Endocrinol Metab.
2000;
85
666-670
- 15
Leibenluft E, Schmidt P J, Turner E H, Danaceau M A, Ashman S B, Wehr T A, Rubinow D R.
Effects of leuprolide-induced hypogonadism and testosterone replacement on sleep,
melatonin and prolactin secretion in men.
JClin Endocrinol Metab.
1997;
82
3203-3207
- 16
Luboshitzky R, Lavi S, Thuma I, Lavie P.
Testosterone treatment alters melatonin concentrations in male patients with gonadotropin-releasing
hormone deficiency.
J Clin Endocrinol Metab.
1996 a;
81
770-774
- 17
Luboshitzky R, Wagner O, Lavi S, Herer P, Lavie P.
Decreased nocturnal melatonin secretion in patients with Klinefelter's syndrome.
Clin Endocrinol.
1996 b;
45
749-754
- 18
Luboshitzky R, Dharan M, Goldman D, Herer P, Hiss Y, Lavie P.
Seasonal variation of gonadotropin and gonadal steroid receptors in the human pineal
gland.
Brain Res Bull.
1997;
44
665-670
- 19
Luboshitzky R, Lavie P.
Melatonin and sex hormones interrelationships - a review.
J Pediatr Endocrinol Metab.
1999;
12
355-362
- 20
Luboshitzky R, Levi M, Shen-Orr Z, Blumenfeld Z, Herer P, Lavie P.
Long-term melatonin administration does not alter pituitary-gonadal hormone secretion
in normal men.
Hum Reprod.
2000 a;
15
60-65
- 21
Luboshitzky R, Shen-Orr Z, Ishai A, Lavie P.
Melatonin hypersecretion in male patients with adult-onset idiopathic hypogonadotropic
hypogonadism.
Exp Clin Endocrinol Diabetes.
2000 b;
108
142-145
- 22
Luboshitzky R, Shen-Orr Z, Nave R, Lavi S, Lavie P.
Melatonin administration alters semen quality in healthy man.
J Androl.
2002;
23
547-554
- 23
Mathews C D, Guerin M V, Wang X.
Human plasma melatonin and urinary 6-sulphatoxymelatonin: studies in natural animal
photoperiod and in extended darkness.
Clin Endocrinol.
1991;
35
21-27
- 24
Okatani Y, Sagara Y.
Amplification of melatonin secretion in women with functional secondary ammenorrhea:
relation to endogenous oestrogen concentration.
Clin Endocrinol.
1994;
41
766-780
- 25
Oriola J, Plesa I, Machuca I, Pavia C, Rivera-Fillat F.
Rapid screening method for detecting mutations in the 21 hydroxylase gene.
Clin Chem.
1997;
43
557-561
- 26
Ozata M, Bulkur M, Bingal N, Beyhan Z, Corakci A, Bolu E, Gundogan M D.
Daytime plasma melatonin levels in male hypogonadism.
J Clin Endocrinol Metab.
1996;
81
1877-1881
- 27
Paoletti A M, Cagnacci A, Orru M, Ajossa S, Gueriero S, Melis G B.
Treatment with flutamide improves hyperinsulinemia in women with idiopathic hirsutism.
Fertil Steril.
1999;
72
448-453
- 28
Rajmil O, Puig-Domingo M, Tortosa F, Viader M, Patterson A G, Schwarzstein D, DeLeiva A.
Melatonin concentration before and during testosterone replacement in primary hypogonadic
men.
Eur J Endocrinol.
1997;
137
48-52
- 29
Rittmaster R S.
Antiandrogen treatment of polycystic ovary syndrome.
Endocrinol Metab Clin North Am.
1999;
28
409-421
- 30
San Martin A, Bogdan A, Touitou Y.
Day-night differences in the effects of gonadal hormones on melatonin release from
perifused rat pineals. Evidence of a circadian control.
Steroids.
1996;
61
27-32
- 31
Shurtz E G, Brimer C, Shuetz J D.
Environmental xenobiotics and the antihormone cyproterone acetate and spironolactone
use the nuclear hormone pregnenolone X receptor to activate the CYP3A23 hormone response
element.
Mol Pharamacol.
1998;
54
1113-1117
- 32
Skene D J, Papagiannidou E, Hashemi E, Snelling J, Lewis D F, Fernandez M, Joannides C.
Contribution of CYP1A2 in the hepatic metabolism of melatonin: studies with isolated
microsomal preparations and liver slices.
J Pineal Res.
2001;
31
333-342
- 33
Stefukj J, Hortner M, Ghosh M, Schauenstein K, Rinner I, Wolfler A, Semmler J, Liebmann P M.
Gene expression of the key enzymes of melatonin synthesis in extrapineal tissues of
the rat.
J Pineal Res.
2001;
30
243-247
- 34
Ursing C, Hartter S, Von Bahr C, Tybring G, Bertilsson L, Rojmarl K.
Does hepatic metabolism of melatonin affect the endogenous serum melatonin level in
men?.
J Clin Invest.
2002;
25
459-462
- 35
Venturoli S, Marescalchi O, Colombo F M, Marcelli S, Ravaioli B, Bagnoli A, Paradisi R,
Flamigni C.
A prospective study randomized trial comparing low dose Flutamide, Finesteride, Ketoconazole,
and Cyproterone Acetate-Estrogen regimens in the treatment of hirsutism.
J Clin Endocrinol Metab.
1999;
84
1304-1310
- 36
Voordouw B GG, Euser R, Verdonk R ER, Alberda B J, DeJong F H, Drojendijk A C, Fauser B C,
Cohen M.
Melatonin and melatonin-progestin combinations alter pituitary-ovarian function in
women and can inhibit ovulation.
J Clin Endocrinol Metab.
1992;
74
108-117
- 37
Waldhauser F, Frisch H, Krautgasser G A, Sparotti A, Schober E, Bieglmayer C.
Serum melatonin is not affected by glucocorticoids replacement in congenital adrenal
hyperplasia.
Acta Endocr.
1986;
111
355-359
- 38
Waldhauser F, Boepple P A, Schemper M, Mansfield M J, Crowley W F.
Serum melatonin in central precocious puberty is lower than age-matched prepubertal
children.
J Clin Endocrinol Metab.
1991;
73
793-796
- 39
Wedell A.
Molecular genetics of congenital adrenal hyperplasia (21-hydroxylase deficiency):
implications for diagnosis, prognosis and treatment.
Acta Paediat.
1998;
87
159-164
- 40
White P C, Speiser P W.
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
Endocr Rev.
2000;
21
245-291
- 41
Woo M MM, Tai C J, Kang S K, Nathwani P S, Pang S F, Leung P CK.
Direct action of melatonin in human granulosa-luteal cells.
J Clin Endocrinol Metab.
2001;
86
4789-4797
- 42
Yie S M, Niles L P, Younglai E V.
Melatonin receptors on human granulosa cell membranes.
J Clin Endocrinol Metab.
1995;
80
1747-1749
Prof. R. Luboshitzky
Endocrine Institute
Haemek Medical Center
18101 Afula
Israel
Telefon: + 97246494354
Fax: + 9 72 46 49 55 53
eMail: luboshitzky_r@clalit.org.il