Dual effect of short interval between first and second birth on ductal breast cancer risk in Finland.

OBJECTIVE: A short interval between the first and second birth was associated with an increased risk of advanced ductal breast cancer among women with 5+ childbirths in our previous study. We now evaluated the significance of this risk factor and its relation to the age at first birth among mothers with 2-4 children. METHODS: The cohort of 190,949 Finnish women with 2-4 children comprised 3,834 women with ductal breast cancer diagnosed before 2009. Conditional logistic regression for case-control design nested within the cohort was used to estimate proportional hazard ratios (HR) associated with the birth interval. Controls were matched for age and number of children. Age at the first birth and the interval from the last birth to cancer were co-variables. RESULTS: Among women with the first birth <30 years, the HR of advanced ductal breast cancer at 50+ years for a short (<1.5 years) versus long (>3 years) interval between the first and second birth was 0.48 (95% Confidence Interval 0.33-0.70). Among women with the first birth at 30+ years, the HR of this cancer type diagnosed before the age of 50 years for a short versus long interval between the first and second birth was 5.83 (95% CI 2.30-14.8). CONCLUSION: The interval between first and second birth strongly influences the risk of ductal breast cancer. Because second pregnancy soon after the first one decreased the risk of ductal breast cancer in young primiparas but increased the risk in older primiparas, it is likely that in such circumstances second pregnancy continues the actions initiated by the first pregnancy/breast-feeding.

Birth intervals and breast cancer risk.

BACKGROUND: The interval between successive births (birth interval) may affect breast cancer risk, whereas interval from last birth to cancer onset may modify its behaviour. METHODS: The study cohort consisted of 29 488 Finnish grand multiparous (GM) women, including 628 women with breast cancer. Conditional logistic regression for case-control design nested within the cohort was used to estimate proportional hazards (referred as relative risks, RR). Age at first birth and parity were co-variables. RESULTS: Short interval (<1 year) between first and second birth increased the risk of advanced ductal breast cancer at ages < 50 years (RR=5.29; 95% CI 2.00-14.0) as compared to interval 3+ years. The risk of advanced ductal cancer was also large (RR = 4.00; 95% CI 1.19-13.4) shortly (<3 years) after last birth as compared with the period 15+ years. CONCLUSIONS: Short birth interval-associated excess breast cancer risk may be related to stimulatory effects of female steroid hormones produced during two closely connected pregnancies, or defective breast maturation owing to failures in breastfeeding.

Amino-terminal propeptide of type III procollagen: a new prognosis indicator in human ovarian cancer.

To investigate the clinical usefulness of the amino-terminal propeptide of type III procollagen (PIIINP) as an indicator of ovarian cancer behavior, 30 patients with advanced epithelial malignancy were monitored with serial serum PIIINP and CA-125 determinations before and during treatment. Initially, PIIINP and CA-125 concentrations were each separately increased in 87% of the cases and, simultaneously, in 77% of the cases. In monitoring treatment responses, PIIINP and CA-125 were identical in 17 patients (57%), both being good predictors of the clinical behavior of the disease in 16 cases and poor predictors in one case. In 13 patients (43%) they were complementary to each other. In three cases PIIINP alone and in one case CA-125 alone were clinically useful prognosis indicators. During the period of complete clinical response to cytotoxic chemotherapy of 16 patients, the CA-125 concentrations decreased to normal before the clinical disappearance of the tumor in eight cases. PIIINP did so in only two cases, thus correlating more precisely with the presence of malignancy. In second-look laparotomies, PIIINP concentrations correlated with the presence of occult cancer better than those of CA-125. In predicting recurrent malignancy in patients with transient complete response, PIIINP and CA-125 were clinically equal. According to the present data, PIIINP concentrations often give information not obtainable by CA-125, thus being useful in monitoring the clinical behavior of ovarian cancer.

Progressive ovarian carcinoma induces synthesis of type I and type III procollagens in the tumor tissue and peritoneal cavity.

Increased serum concentrations of aminoterminal propeptide of type III procollagen occur in advanced ovarian cancer. To study their origin, we compared the expressions of type I and type III procollagens in ovarian tumor tissue and the peritoneal cavity with immunoassays for the propeptide domains of these procollagens. Samples of tumor cyst fluid, peritoneal ascitic fluid, tumor vein blood, and peripheral blood were obtained at operation from 50 women with malignant ovarian neoplasms and 61 women with benign neoplasms. The ascitic fluid concentrations of both type I and type III procollagen antigens were significantly higher in the malignant tumors than in the benign ones, but this difference was evident only for type I procollagen in the tumor cysts. The aminoterminal propeptide of type III procollagen concentration in the peripheral blood was higher in the patients with malignant tumors, whereas the concentrations were similar in the tumor veins. The enhanced type I procollagen synthesis in the malignant tumors did not affect the corresponding antigen in the blood. The findings suggest that progressive ovarian carcinoma invariably induces a fibroproliferative response, characterized by active expression of type I and type III procollagens. The increased circulating aminoterminal propeptide of type III procollagen is derived from the peritoneal cavity rather than from the tumor tissue via the ovarian vein.

Prediction of clinical outcome with estrogen and progestin receptor concentrations and their relationships to clinical and histopathological variables in endometrial cancer.

Concentrations of cytosol estrogen (ERC) and cytosol progestin (PRC) receptors were assayed in malignant tissue specimens of 230 patients with endometrial cancer, and those of nuclear estrogen and nuclear progestin receptors, and 17 beta-hydroxysteroid dehydrogenase activities in about 100 specimens. Endometrial cancer was at an early stage in 205 and advanced in 25 patients. As a supplement to surgical and radiation therapy, all patients received p.o. medroxyprogesterone acetate (100 mg a day) for 2 years. The follow-up time varied from 12 to 96 months (median, 42 months). Concentrations of ERC, PRC, nuclear estrogen, and nuclear progestin receptors in endometrial cancer tissue were significantly lower in clinical stages III-IV than in clinical stage I. In clinical stage I, ERC and PRC appeared in significantly lower concentrations in anaplastic than in moderately and well differentiated malignancies. The concentrations of these receptors were increased in obese patients, and the activity of 17 beta-hydroxysteroid dehydrogenase was increased in patients younger than 50 years, suggesting that endogenous female steroid hormones modify the pattern of female steroid receptors in malignant endometrium. In clinical stage I, 13 of 153 patients with adequate therapy contracted a recurrent disease. Poor prognosis was predicted by anaplastic structure of the malignancy (P less than 0.001), low tissue concentrations (0-30 fmol/mg protein) of ERC alone (P = 0.006), PRC alone (P = 0.010), and ERC and PRC simultaneously (P = 0.004). All 101 patients who simultaneously had ERC and PRC in concentrations higher than 30 fmol/mg protein remained disease free for 2 years, whereas all recurrences in patients with receptor-poor tumors appeared during the 2 years of medroxyprogesterone acetate treatment. In clinical stage II, with 30 patients, no prognosis indicators predicted the clinical outcome, whereas in clinical stages III + IV, with 25 patients, low ERC concentrations were associated with a worsened prognosis (P = 0.045). Conclusively, cytosol and nuclear estrogen and nuclear progestin receptor concentrations and 17 beta-hydroxysteroid dehydrogenase activity give valuable information about the endocrine associations in endometrial cancer. Cytosol estrogen and cytosol progestin receptors appeared to be useful predictors of recurrent disease. They also have the potential to distinguish between patients expected to benefit from adjuvant progestin therapy and those expected to be unresponsive to the same treatment.

Type I and III collagen metabolites as predictors of clinical outcome in epithelial ovarian cancer.

We evaluated the significance of biochemical tumor markers, ie, aminoterminal propeptide of type III procoliagen, trivalently cross-linked COOH-terminal telopeptide of type I collagen (ICTP), aminoterminal propeptide of type I procollagen, and CA 125 in the prediction of ovarian cancer outcome and compared them with several classical indicators of prognosis. The concentrations of biochemical markers were determined from the preoperative serum specimens of 55 patients with epithelial ovarian cancer. In the univariate analysis, all biochemical markers except PINP and all conventional prognostic indicators except histological subtype correlated significantly with survival. In the multivariate Cox analysis of biochemical markers, serum ICTP remained the only significant prognostic indicator of overall survival. Among all variables, clinical stage and ICTP were the only independent and significant determinants of prognosis. Because the content of trivalently cross-linked, mature type I collagen (the breakdown of which is detectable in the ICTP test) in malignant ovarian cancer tissue has been reported to be lower and that of bivalently cross-linked and non-cross-linked collagen has been reported to be higher than in benign tumors, the source of excess ICTP in the circulation of ovarian cancer patients is most likely the degradative damage of soft tissues surrounding the progressively growing malignant lesions. The serum ICTP concentration can thus be regarded as an indicator of the invasion of ovarian cancer. Such information is not available by conventional methods. Therefore, the ICTP test will improve the accuracy of predicting clinical outcome in this disease.

Metoclopramide increases prolactin release and milk secretion in puerperium without stimulating the secretion of thyrotropin and thyroid hormones.

To explore the effect of metoclopramide (MC) on the secretion of PRL, TSH, and thyroid hormones (T3 and T4) and on defective lactation, 17 mothers with poor lactation were treated with oral MC (10 mg. three times daily) for 3 weeks starting 18-141 days post partum. After a pause of 1 week, the medication was given for a further 2 weeks. The breast milk yield was monitored objectively before and during the trial. Furthermore, iv stimulation tests with MC (10 mg) and TRH (200 microgram) were done before and at the end of oral MC therapies. Oral MC increased the mean (+/-SEM) plasma PRL level from 36.6 +/- 9.2 to 90.6 +/- 7.5 ng/ml (P less than 0.001) after 1 week, and the PRL level remained elevated for as long as MC was administered. During the pause, the PRL level decreased to 19.5 +/- 7.5 ng/ml, but increased once again during the second MC treatment to 85.5 +/- 16.0 ng/ml (P less than 0.01). Plasma TSH, T3, and T4 did not change. The PRL level rose significantly after TRH and MC injections before and during oral treatments with MC, whereas the TSH concentrations were elevated only after TRH stimulation. The PRL response to iv MC or TRH and the TSH response to iv TRH were not affected by oral MC treatment. The mean daily milk volume increased from 433 +/- 55 to 626 +/- 75 ml (P less than 0.001) during the first treatment and from 390 +/- 73 to 606 +/- 56 ml (P less than 0.01) during the second oral MC treatment. Correspondingly, the volume of daily supplemental alimentation decreased from 348 +/- 61 to 280 +/- 59 ml (P less than 0.05) and from 526 +/- 68 to 363 +/- 66 ml (P less than 0.01), respectively. MC caused no significant side effects.

Intraamniotic or intravenous injection of dehydroepiandrosterone sulfate in midgestation: effect on prolactin level in maternal serum and amniotic fluid.

The influence of dehydroepiandrosterone sulfate (DHEA-S) on PRL levels in maternal serum and amniotic fluid at midgestation was evaluated in a series of 32 women admitted for midtrimester abortion. Serum was collected hourly for 6 h in 13 women after intraamniotic (ia) instillation (100--200 mg) or in 10 women after iv injection (100 mg) of DHEA-S, and in 9 control women. Serum PRL levels rose significantly (P less than 0.05) 3--6 h after ia and 2--6 h after iv administration of DHEA-S but was unchanged in the control group. The elevation of serum PRL levels is most likely secondary to increased levels of serum estrogens which accompany ia or iv administration of DHEA-S. This suggests that maternal pituitary PRL secretion is responsive to additional stimulation by endogenous estrogens at midgestation. The amniotic fluid PRL level ranged from 1109-2473 ng/ml, with no consistent change after administration of ia DHEA-S, intimating that estrogens may not be implicated in the control of PRL in amniotic fluid.

Physical exercise-induced changes and season-associated differences in the pituitary-ovarian function of runners and joggers.

The hormonal responses to energetic chronic exercise and to seasonal shift from autumn to spring were evaluated by measuring concentrations of serum FSH, LH, PRL, estradiol (E2), progesterone (P), testosterone (T), and sex hormone-binding globuline (SHBG) during 1 menstrual cycle in the autumn (light training season) and 1 in the spring (hard training season) in 18 endurance runners and 12 age-matched nonrunning women, and in 13 joggers and 11 age-matched nonjogging women. The appearance, growth, and maximal size of the ovarian follicles were monitored by ultrasonography. The high intensity training of the runners was associated with decreased concentrations of FSH on cycle days 7-8 in the autumn, E2 on cycle days 12-13 in the spring and days 22-23 in both seasons, P on cycle days 20-21 in both seasons and days 22-23 in the autumn, and T on cycle days 12-13, 14-15, and 22-23 in the spring. Jogging, however, did not alter the concentrations of these hormones. Using as criteria the presence of 2 or 3 abnormal values of the 3 indicators used for evaluation of folliculogenesis (midfollicular E2 lower than 0.09 nmol/liter, luteal phase P lower than 7 nmol/liter, and peak diameter of the largest ovarian follicle less than 15 mm), seriously disturbed folliculogenesis was found in 50% of the 32 study cycles of the runners and 9% of the 23 cycles of their controls (P less than 0.01). In all four study groups, there was a significant seasonal difference in the concentrations of ovarian hormones, with lowered E2, P, and T levels in the autumn. There were no differences in the serum concentrations of SHBG between the study groups or between the autumn and the spring. High training activity and a dark photoperiod appeared to independently suppress ovarian activity and were not associated with chronic changes in anterior pituitary hormone or SHBG concentrations.

Cyclic clomiphene citrate treatment lowers cytosol estrogen and progestin receptor concentrations in the endometrium of postmenopausal women on estrogen replacement therapy.

Clinical and experimental studies have indicated that a nonsteroidal antiestrogen, clomiphene citrate, might prevent the stimulatory action of estrogens on the human endometrium. To investigate the mechanisms of this effect, the treatment of 19 postmenopausal patients with conjugated estrogens for 6 months was supplemented cyclically for 10 days with clomiphene citrate after every 7 weeks. Ten patients ingested clomiphene citrate alone, whereas 9 patients continued estrogen treatment during clomiphene supplementation. Estrogen and progestin receptors were measured from the cytosol of the endometrium after the first estrogen period and after the first and third clomiphene treatment. The estrogen receptor concentration was significantly lower after both clomiphene supplementation periods than after the initial estrogen administration. The progestin receptor concentration was significantly lower only after the first clomiphene citrate period. The effect of clomiphene citrate was independent of the initial histological appearance of the endometrium and led to atrophy of the endometrium in most of the patients. Because the effect of clomiphene citrate was independent of simultaneous estrogen administration, it acted as a pure antiestrogen in this treatment modality. The relative decreases in estrogen and progestin receptor concentrations on the present treatment regimen were different from those previously found on progestin treatment and most likely occur via different mechanisms. It is not known whether these two treatment types will have additive effects.

Hormonal and clinical effects of ketoconazole in hirsute women.

The effects of ketoconazole on pituitary-ovarian function and adrenal function were evaluated in nine hirsute women treated with 400-1200 mg/day for 1-6 months. High dose (800-1200 mg/day) ketoconazole treatment decreased serum androstenedione, dehydroepiandrosterone, and testosterone (T) concentrations, while that of 17 alpha-hydroxyprogesterone increased, suggesting a steroidogenic block at the level of 17,20-desmolase. The decreased serum T and increased sex hormone-binding globulin concentrations led to a significant decrease in the free androgen index. Serum estradiol, cortisol, and dehydroepiandrosterone sulfate concentrations did not change. The serum LH concentration and the LH to FSH ratio increased during treatment, suggesting a negative feedback effect of T on pituitary LH secretion. The hormonal changes that occurred during high dose ketoconazole therapy persisted during subsequent low dose (400 mg/day) treatment. The therapeutic effect of ketoconazole on hirsutism manifested itself at 6 months. We conclude that ketoconazole reduces excessive androgen production in a dose-dependent manner and decreases the free androgen index in hirsute women; these changes are accompanied by significant alleviation of hirsutism.

Inverse seasonal relationship between melatonin and ovarian activity in humans in a region with a strong seasonal contrast in luminosity.

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.

Serum and amniotic fluid melatonin during human labor.

The serum and amniotic fluid concentrations of melatonin (MT) were measured by RIA during human labor in different conditions related to the type of delivery and the time of the day of delivery. Serum MT concentrations displayed a normal diurnal rhythm, resembling that of nongravid women; the mean concentration [163.8 +/- 149.6 (+/- SD) pmol/L] at night was significantly (P less than 0.001) higher than that during the day (31.4 +/- 16.3 pmol/L). The amniotic fluid MT concentration, which showed a significant positive correlation to the serum MT concentration (r = 0.625; P less than 0.01), also showed an obvious diurnal rhythm; the mean MT concentration was significantly (P less than 0.01) higher during the night [99.3 +/- 59.3 (+/- SD) pmol/L] than during the day (58.9 +/- 33.5 pmol/L). Reverse phase high pressure liquid chromatography confirmed that the amniotic fluid MT immunoreactivity eluated as synthetic MT. During the night the mean amniotic fluid MT concentration [99.3 +/- 59.3 (+/- SD) pmol/L] was significantly (P less than 0.01) lower than that in serum (178.9 +/- 189.6 pmol/L). The progress of delivery, estimated by cervical dilatation, did not affect serum MT concentrations. Induction of delivery by amniotomy and/or oxytocin, and operative delivery by cesarean section had no effect on serum MT concentrations. Human MT secretion does not seem to be influenced by the physical stress of labor or endocrine changes associated with parturition. The single factor regulating MT secretion during human delivery appears to be the time of day.

Effects of metoclopramide-induced hyperprolactinemia during early follicular development on human ovarian function.

Nine healthy women, aged 25 to 36 yr, were treated with metoclopramide (MC) (10 mg orally three times daily) from the first to the sixth day of their cycle (treatment A) for two successive cycles (n = 18) and six of these women later received MC from -3 to the fifth day of the menstrual cycle (treatment B) during one or two cycles (n = 10), to investigate the effects of hyperprolactinemia during the early phase of ovarian follicular growth. Comparisons were performed with control cycles in the same women. The treatment cycles were characterized by low serum concentrations of LH during the early follicular phase and at midcycle, low early follicular phase serum testosterone (T) levels and high luteal phase T and free T index values, with no significant differences between A and B treatment modalities. We classified the treatment cycles into two categories, seriously disturbed and normal or only slightly disturbed, on the basis of ultrasonographic findings and midcycle estradiol (E2) and luteal phase progesterone (P) concentrations. Folliculogenesis was seriously disturbed in 11 of the 28 treatment cycles (39%). During these cycles, midcycle serum LH and the LH to FSH ratio were lowered, luteal phase LH and FSH increased, midcycle E2 and luteal phase P and the P to E2 ratio decreased, luteal phase T and the free T index and androstenedione increased, and luteal phase 5 alpha-dihydrotestosterone decreased. During the early follicular phase and at midcycle the ratios of T to E2 and androstenedione to E2 were increased, and at midcycle and during the luteal phase of the cycle the ratio of T to 5 alpha-dihydrotestosterone was increased. These changes in steroid hormones were probably of ovarian origin since the serum concentrations of dehydroepiandrosterone sulfate and sex hormone-binding globulin were similar in seriously disturbed and control cycles. Four of the nine study subjects were hyperprolactinemia sensitive (disturbed folliculogenesis) and five hyperprolactinemia resistant (no disturbance in folliculogenesis). During the control cycles the hyperprolactinemia-sensitive women had significantly higher serum concentrations of T than the other women. The present observations indicate that hyperprolactinemia may impair the development of the ovarian follicles during their recruitment period, especially in women with relatively high serum T levels.

Markers of type I and type III collagen synthesis in serum as indicators of tissue growth during pregnancy.

The concentrations of the carboxy-terminal propeptide of type I procollagen (PICP) and the amino-terminal propeptide of type III procollagen (PIIINP) in serum were followed prospectively as indicators of synthesis of the respective collagens in 266 healthy primiparas during the second and third trimesters of pregnancy. The PIIINP concentration increased 2-fold during the third trimester; the median value was 10.0 micrograms/L at gestational week 40, with a range from 4.6-32.7 micrograms/L (reference interval for nonpregnant women, 1.7-4.2 micrograms/L). A significant increase also took place in the PICP concentration. The frequency distributions of the two parameters were near normal at week 26. They started to broaden out at week 32 and were wide at week 38. In severe preeclampsia, PIIINP tended to increase more than in normal pregnancies of the same duration. The increase in PIIINP correlated significantly with maternal weight gain and the birth weight of the infant, but not with other parameters related to pregnancy or delivery. At gestational week 38, there was a significant correlation between the circulating concentrations of insulin-like growth factor-I and PIIINP or PICP, but not between human placental lactogen and PICP, and only a weak association between human placental lactogen and PIIINP. This suggests that insulin-like growth factor-I is involved in the regulation of type I and type III collagen synthesis during pregnancy.

Luteinizing hormone receptors in ovarian follicles of patients with polycystic ovarian disease.

Wedge resection was performed in 12 patients with polycystic ovarian disease, and cell samples from the cystic follicles were assayed for LH(hCG) receptor using [125I]iodo-hCG as a ligand hormone. Simultaneously to wedge resection, blood samples were taken for serum FSH, LH, 17 beta-estradiol, progesterone, and testosterone RIA measurements. Serum LH was regularly elevated (16.0-57.1 U/liter), whereas FSH (5.2-11.5 U/liter) was within the normal reference range. The LH to FSH ratio was between 2.1-7.8. The 17 beta-estradiol concentrations (0.12-0.23 nmol/liter) were within the normal reference range found during the early follicular phase. Only 3 patients had progesterone levels exceeding the assay sensitivity limit of 0.1 nmol/liter. Ony 3 of the 11 patients assayed for serum testosterone had values exceeding the upper limit of the reference range. Seventy-seven percent of the ovarian follicular samples showed specific binding of [125I]iodo-hCG. The number of receptors in positive samples averaged 0.67 +/- 0.11 fmol/mg homogenate protein, which is clearly lower than that in normal preovulatory follicles. Scatchard analyses revealed a single class of binding sites, with a mean equilibrium association constant of 5.4 X 10(9) M-1 at 37 C. These results suggest that the derangement of follicular development in patients with polycystic ovarian disease probably is not due to the lack of appearance of the LH(hCG) receptor. It is possible that the tonic elevation of serum LH results in a decrease in the number of available receptor sites; this would be one step in the process leading to ovarian changes characteristic of this disease.

Circadian and seasonal variation in human preovulatory follicular fluid melatonin concentration.

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.

Isolated prolactin deficiency in a woman with puerperal alactogenesis.

Idiopathic PRL deficiency was detected in a parturient woman with otherwise normal pituitary function. This PRL disorder first became manifest postpartum when she had no milk production, and oral metoclopramide failed to raise her serum PRL levels. Her second pregnancy occurred spontaneously after 3 yr of attempts to conceive. During the pregnancy, her serum PRL concentration was very low, varying from 4.5-7.8 ng/ml, and the puerperium was again characterized by alactogenesis. During normal menstrual cycles and after iv GnRH, TRH, metoclopramide, and insulin tolerance tests, serum PRL was only rarely detectable by RIA, at very low concentrations. Bioassay results confirmed the PRL deficiency. The results confirm that PRL is necessary for puerperal lactation and suggest that it is needed for normal ovarian function. The present data also suggest that the maternal pituitary is the main source of serum PRL during pregnancy, and the decidua has only a minor contribution in this respect.

Serum selenium and glutathione peroxidase, and plasma lipid peroxides in uterine, ovarian or vulvar cancer, and their responses to antioxidants in patients with ovarian cancer.

The concentrations of serum selenium and plasma lipid peroxides, and the activity of serum glutathione peroxidase (GSH-Px) were measured before any therapy in patients suffering from uterine, ovarian or vulvar cancer, and in association with 1-day combination cytotoxic chemotherapy of ovarian cancer following 1-week supplementation with selenium (96 micrograms/day), vitamin E (300 mg/day), selenium and vitamin E, or placebo. Patients with gynaecological cancer (N = 44) had lower serum concentration of selenium (1.15 +/- 0.04 S.E. mumol/l; P less than 0.05) and serum activity of GSH-Px (404 +/- 13 units/l, P less than 0.01) than the control subjects (N = 56; 1.25 +/- 0.03 mumol/l and 444 +/- 8 units/l, respectively). In association with cytotoxic chemotherapy selenium alone (P less than 0.05), vitamin E alone (P less than 0.05) and both of them together (P less than 0.001) decreased the plasma concentration of lipid peroxides, and the combination of selenium and vitamin E also increased the activity of serum GSH-Px (P less than 0.01). During placebo, cytotoxic chemotherapy did not affect plasma lipid peroxides but it decreased (P less than 0.001) the activity of GSH-Px. Selenium inhibited this effect. Our data suggest that antioxidative mechanisms of patients with gynaecological cancer may be defective and that treatment with selenium and vitamin E results in changes of biochemical factors related to lipid peroxidation.

Estrogen receptor in human myoma tissue.

The occurrence and characteristics of an estrogen receptor in the cytosol of myoma samples from human uteri were investigated employing dextran-coated charcoal and density gradient centrifugation techniques. Receptor binding site concentrations in 24 myoma specimens ranged from 23 to 515 fmol/mg cytosol protein (98+/-108, mean+/-S.D.). In one myoma sample no receptor was found. The apparent equilibrium dissociation constant (Kd) was 1.3 X 10(-10) mol/l for estradiol-17beta. On sucrose density gradient centrifugation, [3H]estradiol was bound by macromolecules with sedimentation rates of 4 and 8 S. The latter component was specific for estrogens, whereas the former contained specific and nonspecific binding sites. Ligand specificity studies were carried out utilizing 30 different steroidal compounds. A good correlation was found between the in vitro binding affinity and the in vivo estrogenic potency of the compounds tested. The cytosol estrogen receptor from myoma had a ligand specificity which closely resembled that of the corresponding receptor in normal human myometrium and endometrium as well as in human breast carcinoma. The myoma estrogen receptor level was compared to that in normal myometrium and endometrium in 13 uterine specimens. The receptor concentrations in cytosol fractions from myoma and myometrium correlated significantly (P less than 0.05), whereas no correlation existed between the receptor levels in endometrial and myoma cytosols. Furthermore, the estrogen receptor content in myoma samples did not correlate to estradiol-17beta levels in the myoma cytosol or serum of the same patient.