Department of Obstetrics and Gynecology, San Raffaele Scientific Institute, University of Milan, Italy
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Abstract |
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Key words: cabergoline/hyperprolactinaemia/ovulation induction/PCOS
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Introduction |
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Furthermore, a transient rise in plasma prolactin (PRL) concentrations can be observed during the late follicular and luteal phases of both natural and stimulated cycles (Doldi et al., 2000). It is known that hypothalamic dopamine is the major inhibitor of PRL secretion in humans (Webster, 1999
) and there may be a possible, if controversial, role for central dopaminergic mechanisms in the release of LH. Several investigators (Falaschi et al., 1986
; Prelevic et al., 1987
) also indicated a dopaminergic control on gonadotrophin secretion, and suggested that a reduction of the dopamine inhibitory effect might cause abnormal PRL and LH release, as found in hyperPRLPCOS patients. Few studies have analysed the effect of treatment with a dopamine agonist on the ovarian response of patients with polycystic ovarian changes and mild, elevated serum PRL concentrations.
In order to better understand the influence of dopaminergic control in PCOS, we retrospectively evaluated the clinical effect of cabergoline, a potent dopamine agonist and inhibitor of PRL secretion, on ovarian response (ovarian size, number of follicles developed, peak oestradiol at HCG administration) during recombinant FSH (rFSH) stimulation protocols in such patients.
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Materials and methods |
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All the women fulfilled our criteria for the diagnosis of PCOS: a history of anovulatory infertility and/or oligomenorrhoea or amenorrhoea, a FerrimanGallwey score >7 for hirsutism, hyperandrogenaemia, elevated concentration of LH or an LH/FSH ratio of 2, increased ovarian volume and
10 follicles of 28 mm in diameter at ultrasound examination. They all had mild, increased serum PRL concentrations (mean 31.5 ± 3.1 ng/ml) measured in the mid and/or late follicular phase and in the mid luteal phase of the menstrual cycle before ovarian stimulation. No organic lesion (serum PRL values >50 ng/ml) or medication was responsible for the increased PRL concentrations.
Eighteen patients (group A: mean PRL concentration = 32.8 ± 3.6 ng/ml) were treated with cabergoline (Dostinex® tablet, 0.5 mg, 1/2 tablet per week) before ovarian stimulation, up to the decrease of plasma PRL concentrations (12.5 ± 2.8 ng/ml), and continued the therapy during the long protocol ovarian stimulation.
Twenty-six patients (group B: mean PRL concentration = 31.1 ± 3.2 ng/ml) underwent an ovarian stimulation programme without treatment of hyperprolactinaemia.
Stimulation protocol
All women were treated by a long protocol. It consisted of gonadotrophin-releasing hormone (GnRH) agonist (Triptorelin, Decapeptyl®, IPSEN) at the dose of 0.1 mg/day s.c., administered on day 21 after a progestin-induced withdrawal bleed or spontaneous menstruation.
At the next menstrual flow the oestradiol serum concentration was measured and ultrasound examination of the ovaries performed. If oestradiol plasma concentration was <60 pg/ml and there were no follicles or cyst >10 mm diameter, gonadotrophin treatment was started. If ovarian quiescence was not achieved, a further examination was performed 1 week later.
Gonadotrophin stimulation consisted of one ampoule per day of FSH (rFSH, Gonal-F 75 UI®, Serono, Rome, Italy) for the first 57 days (low dose scheme for PCOS treatment).
Adjustment of the dose (increase of 37.575 UI of rFSH) was based on the individual response. Final maturation of the oocyte was effected with 5000 UI of human chorionic gonadotrophin (HCG, Profasi®, Serono, Rome, Italy) when there were at least 2 follicles >16 mm.
Intra-uterine insemination was performed 3236 h after HCG administration.
Statistical analysis
All results are reported as the mean ± standard deviation. Differences in the mean values for individual hormone measurements were assessed by using analysis of variance and the two-tailed group t-test.
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Results |
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Discussion |
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Cabergoline, a new long-acting ergoline D2 agonist derivative, has been in use for six years. Compared with other dopamine agonists, it seems that cabergoline is well tolerated and appears to have similar efficacy in PRL suppression and restoration of gonadal function (Paoletti et al., 1994; Ciccarelli et al., 1997
; Webster, 1999
). Furthermore, no increase in miscarriage rate, congenital malformation, distribution of birthweights and sex ratio within the expected range was observed (Robert et al., 1996
). Clinical data concerning dopamine influence on gonadotrophin release, in particular LH, are still controversial.
Although the mechanism is not clear, many authors (Klibanski et al., 1984; Falaschi et al., 1986
; Chapman et al., 1987
; Matsuzaki et al., 1994
; Paoletti et al., 1996
) have demonstrated an inhibitory role of dopamine, and its agonists, on LH secretion and androgen concentrations both in normal and hyperPRL women. According to its capacity to reduce LH secretion, dopamine agonists were proposed as a useful tool in the management of PCOS (Falaschi et al., 1986
; Isik et al., 1997
).
The aim of our study was to evaluate PCOS patients with mild increased serum PRL concentrations who were participating in an ovulation induction programme, and to quantify the clinical effect of cabergoline on the outcome of ovarian stimulation. We compared mild hyperPRLPCOS patients (group A) treated with the dopamine agonist cabergoline during rFSH/HCG administration with untreated hyperPRLPCOS patients (group B).
We found that: (i) despite a reduced total number of ampoules of rFSH and fewer days to reach HCG administration, peak oestrogen plasma concentrations were significantly higher in the untreated hyperPRLPCOS patients; (ii) by ultrasound examination, group B presented a significantly higher ovarian volume and an increased total number of follicles of every size; (iii) four cases of ovarian hyperstimulation syndrome lead to the suspension of treatment in group B compared with only one case in group A; (iv) no significant differences were observed either in cumulative pregnancy rate or in multiple pregnancy rate.
Our data support the evidence of a dopaminergic component in the control of LH release in PCOS patients, and suggest that a pre-treatment with cabergoline reduces ovarian response to rFSH, without affecting pregnancy rate or increasing the possibility of multiple pregnancy. Although these data are not statistically significant, this approach should be further investigated as a potentially important option for limiting the risk of OHSS in the clinical handling of such patients.
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Notes |
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References |
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Submitted on March 30, 2001; accepted on August 7, 2001.