1 Department of Obstetrics and Gynaecology and 2 Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland
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Abstract |
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Key words: cancer/infertility/menopause/ovulation induction/parity
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Introduction |
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Our university hospital serves approximately one-fifth of the total population of Finland, and is a tertiary clinic for infertility and cancer treatment. We analysed the reproductive features of women with GCT diagnosed at our hospital, and compared those diagnosed at a potentially fertile age with those diagnosed later in life. In addition, we compared the frequencies of major features with population-based data.
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Materials and methods |
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Women with GCT at a fertile age (from 16 to 45 years) were identified and an analysis with reference to a possible use of ovulation inducers (available from 196667 in Finland) was performed. The results were compared with two population-based databanks: (i) the fertility data of a national fertility survey of 5105 Finnish women aged 22 to 55 years in 1989 (Nikander, 1992; see their Table I:c, the primary infertility rate of the survey was based on the answers of 836 nulliparous women aged under 40 years, who were non-users of contraceptives, to the question `why do you not yet have children of your own?'); and (ii) a study on the incidence of infertility of 4730 women aged 30, 35 and 40 years participating in a screening programme for cervical cancer in the Helsinki area in 1982 (Rantala and Koskimies, 1986
). The total infertility rate in this study consisted of actual and previous infertility determined as unachieved desired pregnancy within at least one year of unprotected intercourse. Menopause was defined as cessation of menstruation, as in the survey of 2000 women aged 45 to 64 years in 1989 (Topo and Hemminki, 1995
). The other population-based references are given in Table I
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Results |
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The most common signs of the tumour in women with a uterus was oligo-amenorrhoea (45%) if GCT was diagnosed at fertile age, and dysfunctional bleeding (71%) if the tumour was diagnosed at an older age. In postmenopausal women (n = 84), GCT was diagnosed on average 13 ± 9 (SD) years after menopause (Figure 2C). Four women (5%) were thought to have premature menopause (before the age of 40). Signs of hyperoestrogenism determined by elevated preoperative urine or serum oestrogens concentrations (high compared with references used at that time) were found in 14 postmenopausal of the 18 evaluated (78%). Papanicolau smear in postmenopausal women not using oestrogen therapy revealed an increased oestrogen index (>1) in 27 out of 53 samples (51%). Serum FSH concentrations were low (<40 IU/l) in three out of seven postmenopausal patients studied.
Hyperplasia of the endometrium occurred at all ages, but was much more frequent if GCT was diagnosed after the age of 45 (Table I). Cancer of the endometrium was detected only in women with GCT after fertile age (from 54 to 78 years) (P < 0.0001), and had been the indication for surgery in four cases. Hysterectomy prior to diagnosis of GCT was performed in 11 (8%) women, two of whom developed GCT at fertile age. Hysterectomy had been indicated because of fibroids in eight women, an ovarian tumour in one woman (thecoma), uterine malignancy in one, and a descended uterus in one. In addition, two women had undergone unilateral oophorectomy before diagnosis of a GCT at fertile age: one because of an ovarian dermoid cyst 7 years earlier, and the other because of an extra-uterine pregnancy 20 years earlier. Two women had repeatedly been operated on for endometriosis prior to subsequent GCT and one woman had concomitant ovarian endometriosis with GCT (in this case without a history of infertility). Breast cancer prior to GCT was diagnosed in four women, two of them at fertile age. The time elapsed between breast cancer and GCT varied from 4 to 10 years.
Thirteen women (13%) were past users of oral contraceptives (used from 3 months up to 10 years). Cyclic progestin had been prescribed for 16 premenopausal women (16%), but hormone replacement therapy was prescribed only for eight postmenopausal women (10%).
No significant changes from decade to decade were noted in the age, menopausal status or parity in women developing GCT. In particular, the number of cases occurring at fertile age remained similar over the decades [24% (12/50) in 195666; 28% (14/50) in 196776; 22% (11/50) in 197786; and 26% (13/50) in 198796].
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Discussion |
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The rate of anovulatory infertility among infertile couples with GCT (58%, 7/12) was high compared with the commonly given rate of one-third of infertile couples without GCT (Rantala, 1988). It seems likely that the hormonal effect of a GCT disturbs the menstrual cycle, producing oligo-amenorrhoea and anovulatory infertility, and this leads to the patient using ovulation inducers. The five users in this series represent 4.2% of all the cases diagnosed after introduction of these drugs (i.e. 5/118), a value comparable with the frequency of ovarian stimulation of 4.1% in both controls and cases in the large Danish study of ovarian cancer and fertility drugs (Mosgaard et al., 1997
). It is noteworthy that none of our cases had participated in an IVF programme, despite ready availability. The use of ovulation inducers in our patients lasted from one to nine cycles, and the tumours presented mainly at or within a year from the start of medication (3/5; Table II
). Thus, a causative link between GCT and ovulation inducers seems unlikely, but the possible stimulatory effect on the growth of an existing tumour remains possible. The effect of GCT on fertility is further supported by the100% rate of spontaneous pregnancies after tumour removal in the previously infertile women with intact uterus. This improved fertility after surgery was also evident in a previous series (Willemsen et al., 1993
). Reported ongoing pregnancy rates with GCT have been 1.41.7% of untreated cases (Evans et al., 1980
; Ohel et al., 1983
), corresponding well to the 2% of our series.
Age at menarche and menopause, and the mean body mass index, have not differed from population means in reported series (Widholm and Kantero, 1971; Topo and Hemminki, 1995
). Although the peak serum gonadotrophin concentrations occur at about 5 years after the menopause (see Jansen, 1992, for review), only 21% of the GCT in postmenopausal women were diagnosed within this time (Figure 2
), and about half were diagnosed within 13 years from menopause. Early menopause has been suspected of being a sign of ovarian pathology (Melica et al., 1995
), but this occurred in only 5% of our cases.
The 8% rate of endometrial cancer and 30% rate of endometrial hyperplasia are in concordance with earlier studies and are explained by hyperoestrogenism. These findings indicate that an endometrial sample is always necessary with GCT. However, no woman under 45 years presented with endometrial cancer. This is in concordance with a summary of 926 case reports of GCT from the early 1950s with no endometrial cancer reported in women under 40 years of age (Diddle, 1951). Breast cancer was diagnosed before GCT in 3% of women, all of whom had clear signs of hyperoestrogenism at diagnosis of GCT. A recent report of a growing endometrial cyst and multiple fibroids complicated by GCT also highlights the potential clinical difficulty in diagnosing GCT when other gynaecological pathology is present (Kurioka et al., 1998
).
In conclusion, the main reproductive associations and consequences of patients with GCT appear not to have changed during the past few decades. Nulliparity is more common than in the general population, significantly so in women diagnosed with GCT at fertile age. A high rate of infertility, especially anovulatory infertility, is associated with GCT occurring at fertile age. However, the use of ovulation-inducing drugs was not greater than expected in this series. These findings, together with the 100% rate of spontaneous pregnancies after tumour removal, support the theory that the existing tumour, rather than ovulation inducers, is the link between infertility and GCT.
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Acknowledgments |
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Notes |
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References |
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Submitted on June 28, 1999; accepted on November 22, 1999.