The hormonal background of endometrial cancer is insufficiently characterised. We investigated the significance of parity, age at first birth, intensity between births, length of time from the first to the last birth and length of delivery-free premenopausal period in a cohort of grand multiparous (GM) women, i.e., women with at least 5 births. Data of the Population Register of Finland (86,978 GM-women) and the population-based Finnish Cancer Registry were combined. Standardised incidence ratios (SIRs) were calculated by dividing the number of observed cancer cases by the expected number based on the national incidence rates. Key words: endometrial cancer; age at first birth; parity; grand multiparity; birth periodEndometrial cancer is a hormone-dependent malignancy. Unopposed estrogen promotes malignant transformation of the endometrium, an action that is counteracted by progesterone. 1 Pregnancy is characterised by continuous progesterone production from the early weeks of gestation until delivery. 2 Possibly for this reason, at least partly, parous women have a markedly lower risk of endometrial cancer than nulliparous women. [3][4][5][6][7][8] The term grand multiparity (GM) defines women who have undergone at least 5 full-term pregnancies. 9 The Population Register of Finland contains detailed information on the births and children of all GM mothers. Using this national population register of GM-women and data of Finnish Cancer Registry, we studied the significance of parity, age at first birth, average intensity between births, birth period and premenopausal delivery-free period as risk determinants of endometrial cancer. MATERIAL AND METHODS Population-based registersThe computerised files of the Finnish Population Register, which includes links between parents and their children who were living at the same address in 1974 or later, revealed 86,978 GMwomen during the period 1974 until the end of 1997. Follow-up for endometrial cancer was done automatically through the files of the national, population-based Finnish Cancer Registry with personal identifiers. Follow-up for cancer started on 1 January 1974 or at the birth of the fifth child, whichever was later, and ended at death, emigration or on 31 December 1997, whichever was first. There were 1.68 million person-years in the study. The mean length of follow-up was 19.3 years.The cancer registry data also included information about the histopathologic diagnosis made by local pathologists and clinical stage at diagnosis. Statistical methodsCases of endometrial cancer and person-years at risk were counted by 5-year age groups and separately for 4 parity categories (5, 6, 7 and 8ϩ children), 4 categories by age at first birth (Ͻ20, 20 -24, 25-29 and 30ϩ years) and 3 birth-intensity categories (average interval between the first 5 deliveries Ͻ2.0, 2.0 -3.0 and Ͼ3.0 years). Age at follow up of cancer was categorised into 3 groups, Ͻ50 years ("premenopausal" women), 50 -64 years ("postmenopausal" women) and 65ϩ years. For women 50 years or older, most of who...

The concentrations of melatonin in 112 preovulatory follicular fluid (FF) samples obtained from 60 women undergoing in vitro fertilization and 27 patients at laparotomy during a spontaneous cycle were measured by RIA and compared with those in peripheral serum. The circadian and seasonal variations in FF melatonin were also analyzed. The FF melatonin concentrations in stimulated (mean +/- SEM, 61.9 +/- 6.4 pmol/L) and spontaneous cycles (98.1 +/- 8.9 pmol/L) were significantly higher (P less than 0.005) than those in peripheral serum (25.4 +/- 1.2 and 38.6 +/- 1.8 pmol/L, respectively), and in the stimulated cycles there was a positive correlation between them. The FF melatonin concentration in the morning (58.9 +/- 3.8 pmol/L) was significantly higher (P less than 0.005) than that in the daytime (23.2 +/- 0.8 pmol/L), but the morning concentrations did not differ between the light and the dark seasons of the year, whereas the daytime values were higher (P less than 0.005) during the dark season (27.1 +/- 2.1 pmol/L) than during the light season (21.1 +/- 2.1 pmol/L). The FF melatonin concentration did not correlate with follicular volume, and FF and serum melatonin concentrations showed no significant correlation with the serum concentrations of estradiol, progesterone, testosterone, or PRL. There were also no differences between FF melatonin concentrations in aspirates with or without an ovum. In summary, significant circadian and circannual variations in high FF melatonin concentrations were found, which suggest that melatonin could potentially interfere with the regulation of reproduction in humans at the follicular level.

A prospective, double-blind, placebo-controlled study was designed to evaluate the clinical efficacy and tolerance of danazol and high-dose medroxyprogesterone acetate (MPA) in the treatment of mild-moderate endometriosis. After laparoscopical confirmation of endometriosis, 59 patients were randomized to receive danazol (200 mg 3 times daily), MPA (100 mg daily) or placebo for 6 months. Clinical examinations were done before and 1, 3, 6 and 12 months after the beginning of the study, and a 2nd laparoscopy 6 months after termination of the medication. Eighteen patients in the danazol group, 16 in the MPA group and 17 in the placebo group completed the trial. Total or partial resolution of peritoneal implants was observed in 60% of the patients receiving danazol and in 63% of the patients receiving MPA. In the placebo group, resolution was observed in 18%, while the size of the implants was estimated to be increased in 23% of the patients. In relation to placebo, danazol and MPA significantly alleviated endometriosis-associated pelvic pain, lower back pain and defecation pain, but they did not differ from each other in these actions. The appearance of acne, muscle cramps, edema, weight gain and spotting bleeding complicated MPA treatment. The present results indicate that because of good efficacy and tolerance, high-dose MPA is a useful alternative in the hormonal treatment of endometriosis.

The effects of season on the activity of the pituitary-ovarian axis and the pineal gland were studied in 11 women by serum and urinary melatonin determinations and in 21 women by measurements of the serum concentrations of anterior pituitary and ovarian hormones during the dark and light seasons. A melatonin index was determined by integration of the area below the curve of serum melatonin concentrations during 24-h periods in both seasons. During the dark season, the daytime 12-h melatonin index and daytime urinary melatonin excretion were significantly higher than during the light season. In addition, the duration of the nocturnal melatonin pulse (serum melatonin levels, greater than 65 pmol/L) was lengthened during this season, whereas the mean serum estradiol concentration was significantly decreased at the time of ovulation and during the luteal phase of the cycle, indicating lowered ovarian activity. Luteal phase gonadotropin concentrations were increased during the dark season, which was also characterized by increased sex hormone-binding globulin (SHBG) and decreased free testosterone concentrations and free androgen indices (ratio of testosterone to SHBG X 700) throughout the menstrual cycle. The dark season was thus characterized by increased melatonin secretion and decreased ovarian and androgenic activities. In summary, we characterized two season-dependent hormonal phenomena. Although we did not prove any cause and effect association between melatonin and anterior pituitary-ovarian hormones, the inverse seasonal relationship in pineal gland and ovarian secretion suggests that melatonin is causally related to reproduction in humans.

NOTE.-Phosphomannomutase and protein were measured as described elsewhere (Van Schaftingen and Jaeken 1995; Jaeken et al. 1997a). Phosphomannose isomerase was assayed at 30ЊC in a reaction mixture (1 ml) containing 50 mM Hepes, pH 7.1, 5 mM MgCl 2 , 25 mM KCl, 1 mM dithiothreitol, 0.6 mM NAD ϩ , 0.5 mM mannose 6phosphate, 2.5 U/ml glucose 6-phosphate dehydrogenase from Leuconostoc mesenteroides, and 10 mg/ml phosphoglucose isomerase with 10 ml of an extract containing 5-20 mg protein/ml. Control and PMM deficient measures are mean values ‫ע‬ SD. Where two data are given, the values were obtained on two different subcultures.