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.

A population-based study on the risk of cervical cancer and cervical intraepithelial neoplasia among grand multiparous women in Finland.

Previous studies suggest that high parity increases the risk of cervical cancer. We studied the risk of cervical cancer (CC) and cervical intraepithelial neoplasia (CIN3) in a Finnish cohort of grand multiparous (GM) women (at least five children) with low prevalence of sexually transmitted infections (STI). The Finnish Cancer Registry data revealed 220 CC and 178 CIN3 cases among 86 978 GM women. Standardised incidence ratios (SIR) were calculated from the numbers of observed and expected cases. Interval analyses by parity, age at first birth and average birth interval were done using multivariate Poisson regression. Seroprevalence of human papillomavirus (HPV) 16 and Chlamydia trachomatis was tested among 561 GM women and 5703 women with 2-4 pregnancies. The incidence among GM women was slightly above the national average for squamous cell carcinoma of cervix uteri (SIR 1.21, 95% CI 1.05-1.40) and CIN3 (1.37, 95% CI 1.17-1.58), but lower for adenocarcinoma (SIR 0.77, 95% CI 0.52-1.10). The seroprevalence of HPV16 and Chlamydia trachomatis among GM women was lower than in the reference population, except among those women who had their child under age 19. Age under 20 years at first birth increased the risk of CC and CIN3 especially in premenopausal GM women, while increasing parity had no effect. The small relative risks of CC and CIN3 among GM women in our study as compared to studies from other countries can be explained by the exceptionally low prevalence of STIs in Finnish GM women. The observed SIRs between 1.2 and 1.4 should be interpreted to represent increased risk attributable to grand multiparity. The increased incidence of CC and CIN3 among young GM women suggests causal association to HPV 16 and Chlamydia trachomatis infections.

Effect of short-term antenatal dexamethasone administration on type I collagen synthesis and degradation in preterm infants at birth.

UNLABELLED: To assess the effects of antenatal corticoid administration on foetal collagen metabolism, cord serum concentrations of the aminoterminal propeptide and carboxyterminal telopeptide of type I procollagen (PINP and ICTP), which reflect rates of type I collagen synthesis and degradation, respectively, were measured in 67 consecutive preterm infants with gestational ages ranging from 24 to 32 wk. The samples were divided into three groups, depending on the administration and timing of antenatal corticosteroid treatment for enhancement of foetal lung maturity: cases in which the mothers had received a full 2-dose administration of dexamethasone on consecutive days 1 to 6 d before delivery (n = 23; Complete-Dexa), those who had received only a single dose of dexamethasone less than 24 h before delivery (n = 17; Partial-Dexa) and those who had not received any antenatal steroids (n = 27; No-Dexa). Infants in the Complete-Dexa group had significantly lower median PINP levels than those in the No-Dexa group (3,326 vs 4,028 microg/l; p = 0.036); the median PINP level in the Partial-Dexa group (3,999 microg/l) was close to that of the No-Dexa group. No significant differences in ICTP concentrations were seen between the groups. CONCLUSION: A significant suppression of foetal collagen synthesis but not degradation was found to be associated with antenatal dexamethasone administration. This should be taken into consideration, e.g. when assessing whether to administer repeated or single courses of corticosteroids antenatally in high-risk pregnancies.

Grand multiparity and the risk of breast cancer: population-based study in Finland.

OBJECTIVES: The significance of reproductive factors on breast cancer risk has so far been characterized in populations with 5-paras as the highest category of parity. We extended these studies to a nationwide cohort of women with at least five births (grand multiparas = GM) by assessing the significance of parity, age at first birth, and average birth interval to the risk of breast cancer. METHODS: The study cohort obtained from the Population Register of Finland comprised 86,978 GM-women; the incidence of cancer cases was obtained from the populated-based Finnish Cancer Registry. During a follow-up of about 2 million person-years, 1508 breast cancers were obtained. Standardized incidence ratios (SIRs) were calculated by dividing the number of observed cases by the number expected on the basis of national rates. RESULTS: In the GM cohort the incidence of breast cancer was low (SIR 0.55, 95% confidence interval 0.52-0.58). The relative risk decreased significantly from 5-paras (SIR 0.60, adjusted for the other study variables) to 8-paras (SIR 0.40). The increase in the age at first birth from less than 20 years to 30+ years nearly doubled the risk (SIR from 0.40 to 0.73). Parity was a significant risk determinant only in ductal cancer, while shortening the birth interval was protective only in lobular cancer. The incidence of advanced breast cancer among GM-women exceeded the population rate in premenopausal women and in women with first birth at the age of 30 years or more. CONCLUSIONS: Our study demonstrated that young age at first birth and increasing number of births were independent and powerful protective factors from the fifth child onwards, while birth interval was weak in this respect. The tumor morphology and the clinical advancement of malignancy modified the dependence of breast cancer risk on reproductive variables.

Carboxyterminal telopeptide of type I collagen (ICTP) in predicting prognosis in epithelial ovarian cancer.

OBJECTIVE: The aim of this study was to assess the prognostic value of serum carboxyterminal telopeptide of type I collagen (ICTP) in ovarian cancer. Serum CA125 was used as a reference marker. METHODS: Forty-five patients with epithelial ovarian cancer were monitored with serial measurements of serum concentrations of ICTP, a degradation product of type I collagen likely to come about via the matrix metalloproteinase pathway. RESULTS: The patients with a good prognosis had significantly lower serum ICTP concentrations than the patients with a poor prognosis both before the operation and at all the postoperative time points studied (3, 6, 9, 12, 18, and 24 months), whereas a corresponding difference in CA125 was first seen after a 12-month follow-up. In multivariate regression analysis, the 9-month serum ICTP concentration remained the only independent prognostic indicator of all biochemical, clinical, and histological variables. The postoperative serum ICTP concentration did not correlate with the clinical stage, the grade of differentiation, or the presence of residual tumor. In contrast to ICTP, postoperative serum CA125 correlated with the clinical stage and the presence of residual tumor. CONCLUSIONS: Because our ICTP test does not detect defectively cross-linked carboxyterminal telopeptides of type I collagen, which is the predominant form in malignant ovarian tissue, the excess ICTP of ovarian cancer patients must originate from the tissue around the tumor, where the malignancy is causing tissue damage. As an indicator of invasion, the serum ICTP test opens up new possibilities to assess the clinical behavior of ovarian cancer and, in the future, also the effect of possible antiproteinase treatment in ovarian cancer.

Type I collagen markers in cord serum of appropriate vs. small for gestational age infants born during the second half of pregnancy.

BACKGROUND: The serum concentration of the N-terminal propeptide of type I procollagen (PINP) reflects the synthesis rate of type I collagen, whereas the corresponding C-terminal telopeptide (ICTP) mirrors its degradation. DESIGN: PINP and ICTP were measured in a total of 690 cord serum samples from 592 appropriate-for-gestational-age (AGA) infants and 98 smal-for-gestational-age (SGA) infants. These markers were compared between AGA and SGA infants of different gestational ages, ranging from 23 to 41 weeks, and birth weights, from 620 to 4555 g. RESULTS: Both PINP and ICTP levels were very high in the preterm AGA infants and declined significantly with advancing gestational age, paralleling the shape of the fetal growth velocity curve. Regardless of the quite large interindividual variations observed in these markers, PINP was significantly lower in both the preterm and term AGA infants than in the SGA infants. This was also the case for ICTP in the preterm infants of gestational age less than 36 weeks. In stepwise multiple regression analyses, gestational age, being either AGA or SGA and head circumference were significant factors to explain the levels of PINP and ICTP. The levels of PINP and ICTP were correlated with each other highly significantly in both the AGA and SGA infants (rs = 0.700 and 0.692, respectively; P < 0.001 in both). CONCLUSIONS: The levels of type I collagen markers seem to follow closely the shape of the fetal growth velocity curve during different stages of gestation. However, because of the large interindividual variations observed, further studies are needed before the significance of these markers for the assessment of normal and abnormal fetal growth can be established.

Loss of heterozygosity at chromosomes 3, 6, 8, 11, 16, and 17 in ovarian cancer: correlation to clinicopathological variables.

Tumor specimens from 78 epithelial ovarian cancer patients were examined for loss of heterozygosity (LOH) at 11 microsatellite markers at chromosomes 3p14.2, 6q27, 8p12, 11p15.5, 11q23.1-q24, 16q24.3, and 17p13.1, to evaluate the involvement, possible clustering, and prognostic significance of these lesions in the progression of the disease. The LOH analysis was performed on polymerase chain reaction (PCR)-amplified DNA from sections of paraffin-embedded tumor and normal tissue pairs. In addition to primary tumors, specimens of metastatic tissues were studied from 19 patients. In the combined results from primary and metastatic tumors, LOH frequencies varied between 31% (6q27) and 69% (17p13.1). Only LOH at chromosomal regions 3p14.2 (D3S1300), 11p15.5 (D11S1318), 11q23.3-q24 (D11S1340 and D11S912), 16q24.3 (D16S476 and D16S3028), and 17p13.1 (D17S938) was associated with an adverse disease course. Our results indicate that LOH at 17p13.1 occurs independently from the other chromosomal sites studied, and is an early event in ovarian tumorigenesis. The LOH at 16q24.3, 11q23.3/q24, and 11p15.5 seems to occur later. The LOH at 11p15.5 and 11q23.3 was associated with reduced cancer-specific survival time; therefore, the studied markers could be located close to genes with influence on patient survival. Of the studied chromosomal regions, the most important tumor suppressor genes involved in the evolution of ovarian cancer appear to be located on chromosomes 11, 16, and 17. The genetic heterogeneity observed in primary and metastatic specimens demonstrates that there are multiple pathways involved in the progression of ovarian cancer.

Serial determinations of aminoterminal propeptide of type III procollagen (PIIINP) and prognosis in ovarian cancer; comparison to CA125.

During malignant growth many changes take place in the metabolism of fibrillar type III collagens in the connective tissues. The aminoterminal propeptide of type III procollagen (PIIINP) has been found to be often elevated in ovarian cancer. In the present study the prognostic value of serum PIIINP concentration in epithelial ovarian cancer is evaluated in relation to serum CA125. Fifty-six women were enrolled in the study. Serial venous blood samples were taken preoperatively and 6, 9 and 12 months after operation for PIIINP and CA125 determinations. The results were correlated to the three-year survival. In Kaplan-Meier survival analysis the preoperative (P = 0.0422), 9-month (P = 0.0062) and 12-month (P = 0.0062) serum PIIINP concentration distinguished between the patients with good and poor prognosis while CA125 did so only at 9- (P = 0.0005) and 12-month (P < 0.0001) follow-up. In the multivariate analysis the independent predictors of prognosis were the preoperative PIIINP and 12-month CA125 concentrations. The percentage changes in serum PIIINP concentration did not differentiate the patients with good or poor prognosis at any time point, whereas the changes in CA125 concentration significantly divided the patients into two prognostic groups during the second half of the postoperative year. We found that PIIINP and CA125 are complementary to each other as predictors of prognosis in epithelial ovarian cancer as preoperative PIIINP was better than CA125 and 1-year CA125 better than PIIINP in this function.

The prognostic value of peritoneal cytology in ovarian cancer.

We studied the significance of peritoneal cytology as a prognostic factor in primary epithelial ovarian cancer. Intraperitoneal specimens for cytological examination were taken from 73 patients at primary operation for ovarian cancer. The prognostic value of cytological findings was analyzed by the Kaplan-Meier method. It was also correlated to clinical stage, tumor histology, histopathological grade, residual tumor, presence of ascites and age by using the chi2-test. The value of cytology in relation to other factors was assessed by Cox-multivariate analysis. In univariate analysis peritoneal cytological findings correlated significantly to survival. In Cox-multivariate analysis peritoneal cytology, histopathological grade and the age of the patient were found to be significant independent prognostic factors in epithelial ovarian cancer. According to this data peritoneal cytology can be considered as an important prognostic factor in ovarian cancer. Therefore it should be evaluated routinely in association with surgery of ovarian tumors.

Transfundal insertion of a Veress needle in laparoscopy of obese subjects: a practical alternative.

Because induction of artificial pneumoperitoneum through the infra-umbilical route is associated with complications in laparoscopic procedures, especially in obese patients, we performed a prospective randomized study comparing the conventional infra-umbilical route with a transfundal route, in which the Veress needle is inserted into the peritoneal cavity through the uterine fundus. One hundred obese subjects (body mass index >/=25 kg/m(2)) scheduled for laparoscopic sterilization were randomized into two groups. In the infra-umbilical group pneumoperitoneum was achieved at a ratio (punctures/pneumoperitoneum) of 56/49 (1.14). There was one failure in this group. In the transfundal group the ratio was 53/51 (1.04). There was no clinically significant bleeding in either of the groups; nor were there any major complications. One subject in whom the infra-umbilical route failed was moved to the transfundal group. This subject also underwent dilatation and curettage at the time of laparoscopy. Postoperatively she contracted chlamydial pelvic inflammatory disease. No other infections were detected postoperatively in either of the groups. In conclusion, the transfundal route of inducing artificial pneumoperitoneum proved to be easy, safe and effective.

The levonorgestrel intrauterine system in menopausal hormone replacement therapy: five-year experience.

OBJECTIVE: To study the long-term effects (5 years) of intrauterine levonorgestrel administration as the progestin part of continuous combined postmenopausal hormone replacement therapy. DESIGN: Prospective clinical study. SETTING: Department of obstetrics and gynecology at a central hospital. PATIENT(S): Twenty postmenopausal women with an intact uterus who had no contraindications to hormone replacement therapy and who wanted to take amenorrhea-inducing hormone replacement therapy to relieve their climacteric symptoms. INTERVENTION(S): A percutaneous E2 gel containing 1.5 mg of E2 was administered daily and a levonorgestrel-releasing intrauterine device was used. Endometrial thickness was measured by vaginal ultrasonography. Endometrial sampling was performed yearly. MAIN OUTCOME MEASURE(S): Clinical compliance, profiles of bleeding, and endometrial thickness and morphology were monitored during 5 years of follow-up. RESULT(S): Eighteen women completed 1 year of follow-up. Fifteen of these women were willing to continue the study, and 12 of them completed 5 years of follow-up. Spotting was frequent during the first 6 months of the study and declined thereafter. At 1 year, 80% of the women were totally amenorrheic. Of the 15 women who continued the study, 12 were totally amenorrheic and 3 had problems with bleeding. The mean endometrial thickness was < or = 3 mm during the study. Endometrial morphology showed epithelial atrophy accompanied by decidualization of the stroma in all 12 of the women who were followed up for 5 years. CONCLUSION(S): Intrauterine administration of progestin through a levonorgestrel-releasing intrauterine device is a good alternative as the progestin part of continuous combined hormone replacement therapy because it effectively opposes the estrogenic effects on the endometrium and induces amenorrhea in most cases.

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.

Chromosome 11q22.3-q25 LOH in ovarian cancer: association with a more aggressive disease course and involved subregions.

Chromosome 11q deletions are common in various malignancies, including ovarian cancer. However, the clinical significance of these genetic lesions as well as their more precise chromosomal location is largely unknown. Here we have examined epithelial ovarian cancer material from 49 patients for loss of heterozygosity (LOH) using nine microsatellite markers on 11q22.3-q25 and evaluated the effect of observed deletions with regard to different clinicopathological variables. LOH was detected in 61% of the patients. Interestingly, LOH for the D11S1340 marker locus at 11q23. 3 seemed to be associated with significantly reduced survival times (P = 0.005) and serous tumor histology (P = 0.036). LOH for D11S912 at the more distal 11q24-q25 location correlated with a higher tumor stage (P = 0.003), serous tumor histology (P = 0.015), and finding of residual tumor (P = 0.047), but not directly with survival times (P = 0.320). The majority of the analyzed tumors simultaneously displayed deletions at two distinct 11q regions, A and B, which are proximal and distal to D11S1347/NCAM (11q23.2-q23.3), respectively. Only LOH for two markers (D11S1340 and D11S912) of the B region seemed to be directly associated with a more aggressive disease course. Therefore, it appears that deletions of the ataxia telangectasia gene of the A region would not be crucial for determining the outcome of ovarian cancer. Our present results indicate that a survival factor gene in ovarian cancer would be located close to D11S1340 at 11q23.3. This corresponds well to our earlier observation in breast cancer, suggesting the involvement of a shared survival factor gene in both diseases.

Lipid effects of an intrauterine levonorgestrel device or oral vs. vaginal natural progesterone in post-menopausal women treated with percutaneous estradiol.

BACKGROUND: The ideal progestin for combined hormone replacement therapy should be free of adverse effects on lipid metabolism. We therefore examined lipid profiles during continuous hormone replacement therapy (HRT) with an estradiol-gel combined with either a levonorgestrel-releasing intrauterine device (LNG-IUD) or oral/vaginal natural progesterone. METHODS: Sixty menopausal women recruited in this open, non-randomised parallel three-group study received percutaneous gel containing 1.5 mg of estradiol daily. Progestin was administered to the women with an LNG-IUD (n = 20), as oral natural progesterone (n = 21) 100 mg daily on the 1-25 calendar days of the month or as vaginal progesterone (n = 19) 100-200 mg daily on the 1-25 calendar days of the month. Serum concentrations for total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and sex hormone binding globulin (SHBG) were measured at 0, 6 and 12 months. The median (and 95% confidence interval) of the serum SHBG, total, LDL-, HDL- cholesterol and triglycerides concentrations at baseline and after 6 and 12 months of the study and the ratio of 6 and 12 months values to baseline values were calculated. RESULTS: Total cholesterol was significantly decreased (8%) in the vaginal progesterone group at the end of the trial. HDL-cholesterol did not change in either of the progesterone groups, while a slight but transient decrease (median 15%) was seen at 6 months in the LNG-IUD group. There were no significant changes in triglycerides or LDL-cholesterol concentrations in any group. SHBG did not change significantly in the LNG-IUD and vaginal progesterone groups, while a slight but transient increase was seen in oral P group at 6 months. CONCLUSIONS: As the only significant harmful effect observed was a transient decrease in HDL-cholesterol in the LNG-IUD group at 6 months, each of these HRT-administration methods can be regarded as being safe in their effects on lipid metabolism.

PIP: This study examined the lipid profiles during continuous hormone replacement therapy (HRT) with an estradiol gel combined with either the levonorgestrel-releasing IUD (LNG-IUD) or oral/vaginal natural progesterone. In an open and nonrandomized parallel three-group study conducted in Finland, 60 menopausal women were administered a percutaneous gel containing 1.5 mg of estradiol daily. Progestin was administered to 20 women with an LNG-IUD, as oral natural progesterone (100 mg daily) to 21 women on calendar days 1-25, or as vaginal progesterone (100-200 mg daily) to 19 women on calendar days 1-25. Serum concentrations of total cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, and sex hormone binding globulin (SHBG) were measured at 0, 6, and 12 months. Results revealed an 8% decrease of total cholesterol in the vaginal progesterone group. HDL-cholesterol remained stable in both progesterone groups, with a 15% decrease at 6 months in the LNG-IUD group. Triglycerides and LDL-cholesterol concentrations were found to have insignificant changes. SHBG was observed to be stable in the LNG-IUD and vaginal progesterone groups, with a slight increase seen in the oral progesterone group after 6 months. This study confirms the safety of this type of HRT with regard to lipid metabolism, except for the transient decrease in HDL-cholesterol among LNG-IUD users at 6 months.

Endometrial morphology during hormone replacement therapy with estradiol gel combined to levonorgestrel-releasing intrauterine device or natural progesterone.

OBJECTIVES: To evaluate endometrial responses to three different forms of amenorrhea-inducing HRT in postmenopausal women. MATERIAL AND METHODS: Fifty-one postmenopausal women completing a one-year HRT trial with percutaneous estradiol gel containing 1.5 mg estradiol daily combined with a levonorgestrel-releasing intrauterine device (LNG-IUD) (n=18), or natural progesterone 100 mg daily orally (n= 19) or vaginally (n=15) during 1-25 calendar days of each month. Endometrial thickness and uterine size were measured by transvaginal ultrasound, and endometrial cytology/histology was assessed from specimens taken by needle aspiration before the study and at 12 months. RESULTS: Before medication, the median endometrial thickness was 2.0 mm in the LNG-IUD group, 2.4 mm in the oral P group and 2.5 mm in the vaginal P group. At 12 months of therapy the respective values, 3.0, 2.7 and 2.4 mm, did not differ significantly from the initial values. LNG-IUD induced epithelial atrophy in all women, which was accompanied by stromal decidualization in 12 women. On the contrary, only four women in the oral P group and five women in the vaginal P group had an inactive or atrophic endometrium. The remaining cases were dominated by proliferative features. No hyperplasia was seen in any of the groups. CONCLUSION: LNG-IUD appeared to be an effective method of counteracting the stimulatory effect of estrogen on the endometrium, whereas natural progesterone given orally or vaginally was not sufficiently effective in this function at the doses used. The vaginal and oral administrations of progesterone did not differ from each other in this respect.

PIP: This study evaluated the endometrial morphological response to the levonorgestrel-releasing IUD (LNG-IUD) and to natural progesterone administered orally or vaginally in postmenopausal women using percutaneous estradiol gel on a daily basis. The study employed 51 postmenopausal women who completed a 1-year hormone replacement therapy trial of 1.5 mg estradiol daily combined with a LNG-IUD (n = 18), 100 mg oral progesterone (n = 19), or 100 mg vaginal progesterone (n = 15) during 1-2 calendar days of each month. Using a transvaginal ultrasound, endometrial thickness was measured prior to and 12 months after the study. Prior to the study, endometrial thickness was 2.0, 2.4, and 2.5 mm for the LNG-IUD, oral progesterone, and vaginal progesterone groups, respectively. During the transvaginal ultrasound (after 12 months) the respective values were 3.0, 2.7, and 2.4 mm, respectively, which was considered normal among postmenopausal women. 12 of the women who were administered the LNG-IUD were found to have epithelial atrophy accompanied by stromal decidualization. On the other hand, 4 women in the oral progesterone and 14 in the vaginal progesterone groups were found to have inactive or atrophic endometrium. Proliferative features dominated the remaining cases, while hyperplasia was not observed in any of the cases. This study confirms the efficacy of the LNG-IUD in suppressing the stimulatory effect of estrogen on the endometrium, while oral and vaginal progesterone were not sufficiently effective at the doses used.

Synthesis and breakdown of fibrillar collagens: concomitant phenomena in ovarian cancer.

The synthesis and degradation of type I and type III interstitial collagens releases several antigenic metabolites, whose measurement allows the metabolism of connective tissue to be evaluated under a variety of different conditions. In this study we investigated the influence of benign and malignant ovarian neoplasms on the metabolism of these collagens. The study population comprised patients with benign (n = 53), borderline (n = 6) or malignant (n = 36) ovarian neoplasms. We quantified the serum, cyst fluid and peritoneal/ascitic fluid concentrations of the amino-terminal propeptide of type I (PINP) and III (PIIINP) procollagens, indicators of the synthesis of type I and III collagen, respectively and the cross-linked carboxy-terminal telopeptide of type I collagen (ICTP), an indicator of type I collagen degradation. Macrophage colony-stimulating factor 1 (CSF-1) concentration was also assayed as its serum level is increased in ovarian cancer and CSF-1 may be involved in the regulation of collagen metabolism. The concentration of each antigen was significantly higher in patients with malignant tumour than with benign neoplasm in each comparison, except for ICTP in peritoneal fluid and for CSF-1 in cyst fluid. The high ascitic fluid concentration of PINP, PIIINP or CSF-1 correlated with malignancy, and the low cyst fluid concentration of any of the four markers was indicative of benign tumour. Levels of CSF-1 did not correlate with the levels of any of the markers of collagen turnover. The concentration of PINP in ascites was about 50 times higher and in cyst fluid about eight times higher than that in the serum from patients with malignant tumour, whereas the respective ratios for ICTP were only 2.5 and 1.3. In such patients, the ratio of ascitic fluid to serum concentration was also about 80-fold higher for PIIINP and about 20-fold higher for PINP than for ICTP. The different distributions of PIIINP, PINP and ICTP suggests dominance of synthetic processes or retarded elimination of PIIINP and PINP in ovarian cancer. In advanced malignancies, the accumulation of PINP and PIIINP in abdominal space, possibly due to increased synthesis and/or failed resorption, may promote ascites formation. This study shows that both accelerated synthesis and breakdown of fibrillar collagens are characteristic of ovarian malignancy, and suggests that measurements of cyst fluid or ascitic fluid concentrations of collagen metabolites or CSF-1 could be used in the differential diagnosis of benign and malignant ovarian neoplasms.

Sex-hormone binding globulin as an indicator of the hepatic impacts of continuous combined hormone replacement regimens.

OBJECTIVES: Nonoral administration of hormone replacement therapy avoids the first pass metabolism of steroids in the liver. We wanted to determine to what extent it has an effect on the serum concentrations of sex-hormone binding globulin and the free testosterone index. METHODS: Postmenopausal women received 50 microg per day transdermal estradiol associated with the use of a levonorgestrel-releasing intrauterine device (20 women) or a daily oral dose of 2 mg of estradiol and 1 mg of norethisterone acetate (20 women) for 1 year. Eight women, five in the nonoral and three in the oral therapy group discontinued the study. RESULTS: Although serum sex-hormone binding globulin concentrations decreased in women receiving transdermal estradiol in combination with a levonorgestrel-releasing intrauterine device, the free testosterone index did not change significantly. In the continuous oral regimen, no significant changes in serum sex-hormone binding globulin or free testosterone index were observed. The free testosterone index, however, was significantly higher in the nonoral therapy group after 6 and 12 months of treatment than in the oral therapy group. CONCLUSIONS: Continuous progestin combined with continuous estrogen in oral and nonoral replacement therapy does not lead to a substantial androgenic excess in postmenopausal women. The intrauterine administration of levonorgestrel appears to have some hepatic effect.