Seppo Saarikoski

HRT and Vit D in prevention of non-vertebral fractures in postmenopausal women; a 5 year randomized trial

OBJECTIVES We investigated the incidence of new non-vertebral fractures during HRT or low-dose vitamin (Vit) D3 supplementation in a 5-year prospective trial. METHODS A total of 464 early postmenopausal women, (a subgroup of the Kuopio Osteoporosis Study, n = 13100) were randomized to four groups: (1) HRT, a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate; (2) Vit D (300 IU/day and 100 IU/day during the fifth year); (3) HRT + Vit D; and (4) placebo. Lumbar (L2-4) and femoral neck bone mineral densities (BMD) were determined by dual X-ray absorptiometry (DXA) at baseline, after 2.5 and 5 years of treatment. All new symptomatic non-vertebral, radiographically defined fractures were recorded. RESULTS Altogether, 368 women (79%) completed the 5 year treatment. In all, 32 women had 39 non-vertebral fractures during a mean of 4.3 year follow-up (HRT 4, Vit D 10, HRT + Vit D 8 and placebo 17). The reduction in the incidence of new non-verterbral fractures was significant in women with HRT alone (P = 0.032) when adjusted by baseline BMD and previous fractures; observed also with the intention-to-treat principle (P = 0.048). When the HRT groups were pooled, HRT showed a significantly lower incidence of new non-vertebral fractures (P = 0.042) than women receiving placebo and also after adjusting as above (P = 0.016); both in valid-case and in the intention-to-treat analysis. In the Vit D group, the fracture incidence was non-significantly decreased (P = 0.229) in comparison with the placebo group. The estimated risk of new non-vertebral fractures among women treated with HRT alone was 0.29 (95% CI, 0.10-0.90) and with Vit D 0.47 (95% CI, 0.20-1.14) and with HRT + Vit D 0.44 (95% CI, 0.17-1.15), in comparison with the placebo group (adjusted by femoral BMD and previous fractures). CONCLUSIONS This study is the first prospective trial confirming the beneficial effect of HRT on prevention of peripheral fractures in non-osteoporotic postmenopausal women. The effect of low-dose Vit D remains to be proved.

Prevalence and risk factors of genital human papillomavirus (HPV) infections in healthy males : a study on finnish conscripts

Background and objectives: Prevalence of genital human papillomavirus (HPV) infection in the general population is not known. No one test alone can detect all HPV infections. Goal of this study: To determine the prevalence of and risk factors for genital human papillomavirus (HPV) infections in healthy males. Voluntary Finnish Army conscripts were examined using peniscopy, cytology (PAP smear) and polymerase chain reaction (PCR) in brush cytology samples. Study design: A total of 1,471 (99.6%) males completed the questionnaire soliciting their sexual habits, and 432 of them enrolled in the clinical study. Results: The study group differed from the nonattenders in that they reported more often genitourinary symptoms (P < 0.001), had more casual sexual partners (P = 0.002), and previous STDs (P < 0.001). Classical genital warts were present in 24/432 (5.6%) and papular lesions in 8/432 (1.9%) males. Acetowhite lesions were disclosed in 151/432 (35.0%) cases, of which 61 (14.1%) had peniscopically typical flat HPV lesions. Koilocytes were found in 13/201 (6.5%) PAP smears. HPV DNA was disclosed by PCR in 16.5% (47/285) of the adequate cell smears, and in 7.1% of the males with no peniscopic abnormalities. When considering the men with HPV‐positive PCR findings and/or typical peniscopic pattern as HPV‐infected (26.2%), many casual partners, previous STDs and no use of condom were significant risk factors for genital HPV infections in the logistic regression analysis. Conclusions: The reliable assessment of the prevalence of genital HPV infections in healthy males is not only skewed by the selection of the study group by symptoms and promiscuity, but also by the lack of a universally acceptable screening method. The data confirm sexual promiscuity as the most important risk factor for genital HPV infections.

Vertical transmission of human papillomavirus from infected mothers to their newborn babies and persistence of the virus in childhood

OBJECTIVE The purpose of this study was to determine the potential for human papillomavirus to be transmitted vertically. STUDY DESIGN We started a systematic study of children 0.3 to 11.6 years old born to mothers included in the cohort of 530 women prospectively followed up for genital human papillomavirus infections in Kuopio since 1981. So far 98 children have been examined. The examinations included medical history, clinical examination of the oral cavity and hand warts, and cytologic samples from the oral mucosa for detection of human papillomavirus deoxyribonucleic acid with polymerase chain reaction with subsequent Southern blot hybridization. RESULTS Human papillomavirus deoxyribonucleic acid was found in 31 of the 98 (31.6%) oral scrapings. with MY09 and MY11 human papillomavirus primers, 12 of the 98 were positive for human papillomavirus deoxyribonucleic acid in the electrophoresis gel and in subsequent hybridization. Nineteen of the positive samples were not visible in the gel but become positive when hybridized. At delivery, 5 mothers had genital human papillomavirus infection with the same virus type found in her child. In the additional 11 mothers genital human papillomavirus infection with the same virus type as in the child was diagnosed a few months before or after delivery. Mothers of the 25 children shown to be negative for oral human papillomavirus were also human papillomavirus deoxyribonucleic acid negative at delivery. Minor hyperplastic growths of the oral mucosa were found in 21 of the 98 children (21%). One child had a papilloma where human papillomavirus 16 deoxyribonucleic acid was detected, as was also found in her mothers genital area at delivery. CONCLUSIONS Our results support the concept that an infected mother can transmit human papillomavirus to her child.

Prevalence, incidence, and estimated life-time risk of cervical human papillomavirus infections in a nonselected finnish female population

&NA; The authors derived prevalence and incidence figures for cervical human papillomavirus (HPV) infections in an unselected Finnish population of women aged 22. This paper is an epidemiologic study utilizing the mass‐screening program that has been conducted in Finland for cervical cancer since the early 1960s. The authors estimated the lifetime risk of cervical HPV infections based on the figures in this program and on those derived from a random sample of 2,084 (out of 28,861) routine Papanicolaou (Pap) smears examined in their laboratory. The mass‐screening program was performed between 1985‐1986 focusing on a total cohort of 22‐year‐old women (born in 1963) in Kuopio province. In 1985, 2,013 women were invited of which 1,289 attended. One year later, 1,768 women of those 2,013 were reinvited, and the number of women screened at the second round was 1,069. The routine cervicovaginal Pap smears were taken, including a cell sample from the vagina, exocervix, and endocervix. All smears were screened for the HPV‐induced cytopathic changes by the same cytopathologist. The prevalence of HPV infection among the 22‐year‐old women was about 3% at the beginning of the follow‐up and about 7% one year later. The crude annual incidence was 7.0%. According to the estimates for the life‐time risk, half of the sexually active women would experience at least one HPV infection within 10 years. Up to 79% of the Finnish females would contract at least one HPV infection between ages 20 and 79 years. This indicates that factors, which are poorly understood at the moment, exist that regulate the development of an invasive carcinoma from a CIS lesion.

Early postmenopausal bone loss is associated with PvuII estrogen receptor gene polymorphism in finnish women : Effect of hormone replacement therapy

Genetic factors regulate bone mineral density (BMD) and possibly the development of osteoporosis. An association between estrogen receptor (ER) polymorphism, BMD, and postmenopausal hormone replacement therapy (HRT) has not been established. Therefore, we studied the influence of the ER genotype on BMD before and after a 5‐year HRT in a placebo‐controlled, population‐based, randomized group of 322 early postmenopausal women. The participants were randomized into two treatment groups: the HRT group (n = 145) received a sequential combination of 2 mg estradiol valerate and 1 mg CPA with or without vitamin D3, 100–300 IU + 500 mg calcium lactate/day (equal to 93 mg Ca2+), and the non‐HRT group (n = 177) received calcium lactate, 500 mg alone or in combination with vitamin D3, 100–300 IU/day. PvuII restriction fragment length polymorphism (RFLP) of the ERα was determined using polymerase chain reaction (PCR). BMDs of the lumbar spine (L2–4) and proximal femur were measured by using dual‐energy X‐ray absorptiometry (DXA). At the baseline, there were no significant differences in the lumbar or femoral neck BMDs between the three ER PvuII genotype groups (PP,Pp,pp). After 5 years, the BMD of the femoral neck remained unaltered and that of the lumbar spine increased by 1.7% in the HRT group, whereas both BMDs were decreased by 4–5% in the non‐HRT group. The ER genotype did not modulate the femoral neck BMD change during the follow‐up. In contrast, in the non‐HRT‐group the lumbar spine BMD decreased more in subjects with the ER genotypes PP (6.4%) and Pp (5.2%) than in subjects with the pp genotype (2.9%) (p = 0.002). In the HRT group, the relative changes of the lumbar spine BMD were similar in all three ER genotype groups. Thus without HRT, the pp genotype was associated with a smaller decrease in the lumbar spine BMD than the Pp and PP genotypes. Long‐term HRT seemed to eliminate the ER genotype‐related differences in the BMD. We conclude that subjects with the ER PvuII genotypes PP and Pp may have a greater risk of relatively fast bone loss after menopause than those with the pp genotype and that they may preferentially derive benefit from HRT. (J Bone Miner Res 2000;15:315–321)

Risk factors for perimenopausal fractures: a prospective study

Abstract: This prospective study was aimed at determining the risk factors for the development of fractures in perimenopausal women. The study group (n= 3068) was comprised of a stratified population sample of women aged between 47 and 56 years. During the follow-up period of 3.6 years, 257 (8.4%) of the women sustained a total of 295 fractures. After adjustment for covariates, the relative risk (RR) of sustaining a fracture was found to be 1.4 [95% confidence interval (CI) 1.2–1.6] for a 1 standard deviation (SD) decrease in the spinal and femoral neck bone mineral density (BMD). Women with a previous fracture history were found to have an increased risk of fracture [RR 1.7 (95% CI 1.3–2.2)] and those reporting three or more chronic illnesses exhibited a RR of 1.4 (95% CI 1.0–1.9). Women not using hormone replacement therapy (HRT) had a RR of 1.5 (95% CI 1.1–2.2) for all fracture types. When osteoporotic fractures (vertebral, hip, proximal humerus and wrist fractures; n= 98) were used as an endpoint, the independent risk factors were found to be a low BMD (RR for a 1 SD decrease in both spinal and femoral neck BMD was 1.6, 95% CI 1.3–2.0), a previous fracture history (RR 1.9, 95% CI 1.3–2.9) and nonuse of HRT (RR 2.2, 95% CI 1.3–4.0). The independent risk factors for all other fractures (n = 158) were a low BMD (RR for a 1 SD decrease in the spinal BMD was 1.4, 95% CI 1.2–1.6 and in the femoral neck BMD was 1.3, 95% CI 1.1–1.5), a previous fracture history (RR 1.6, 95% CI 1.1–2.2), smoking (RR 1.8, 95% CI 1.1–2.7) and having had three or more chronic illnesses (RR 1.6, 95% CI 1.1–2.2). Weight, height, age, menopausal status, maternal hip fracture, use of alcohol, coffee consumption or dietary calcium intake were not independently associated with the development of any particular type of fracture. We conclude that the independent risk factors for perimenopausal fractures are a low bone density, previous fracture history, nonuse of HRT, having had three or more chronic illnesses and smoking, the gradient of risk being similar for spinal and femoral neck BMD measurements in the perimenopausal population. The risk factors are slightly different for perimenopausal osteoporotic than for other types of fractures.

Perinatal diagnostic evaluation of velamentous umbilical cord insertion : Clinical, doppler, and ultrasonic findings

Objective To evaluate the association between velamentous cord insertion and adverse pregnancy outcome in singleton pregnancies, and to assess the diagnostic usefulness of nonstress testing (NST) and Doppler ultrasound in this condition. Methods We retrospectively reviewed 12,750 consecutive singleton, chromosmally normal pregnancies from July 1989 through December 1993 at the University Hospital of Kuopio, Finland. Of these, 216 were complicated by velamentous umbilical cord insertion, whereas the remaining 12,534 were normal controls. Using multiple regression analysis, we evaluated the risks by noting adverse infant outcomes: low birth weight (LBW), small for gestational age (SGA), preterm delivery, fetal death, admission to a specific infant care unit, low Apgar scores, neonatal acidemia, and abnormal intrapartum fetal heart rate (FHR) patterns. At prenatal visits NST and Doppler ultrasound examinations were carried out as a routine part of obstetric care. Results Even after we controlled for confounding factor, velamentous umbilical cord insertion was associated with higher risk of LBW (odds ratio [OR] 2.32), SGA (OR 1.54), preterm delivery (OR 2.12), low Apgar scores at 1 and 5 minutes (ORs 1.76 and 2.47, respectively), and abnormal intrapartum FHR pattern (OR 1.59). Only 5% of the patients with abnormal insertion showed pathologic NST results at prenatal visits. Ultrasonographic examination was carried out on 80 patients with velamentous umbilical cord insertion as a routine part of obstetric care, and in only one case was direct visualization of the abnormal insertion successfull. After we excluded pregnancies with preeclampsia, abnormalumbilical artery Doppler velocimetry was found in none of the cases examined (n = 48). Conclusion There were substantial differences in pregnancy outcome measures between the subjects with velamentous umbilical cord insertion and controls. Current antepartum methods of tracing uteroplacental problems are not effective in the prenatal detection of abnormal insertion. Therefore, in future studies, the use of other diagnostic tools, such as color Doppler imaging of cord insertion, should be evaluated in high-risk pregnancies followed-up because of fetal growth restriction.

The effect of gynecological risk factors on lumbar and femoral bone mineral density in peri- and postmenopausal women

The relationship between gynecological history and bone mineral density (BMD) of the lumbar spine and femoral neck was studied in 3126 perimenopausal women. The study population was a random, stratified sample of participants, selected from the Kuopio Osteoporosis Study, which consisted primarily of all 14,220 women aged 47-56 years in Kuopio Province in 1989. After exclusion of 1521 women reporting past or present hormonal replacement therapy (HRT), 1605 women formed the final study population. Present HRT users had significantly higher lumbar BMD but not femoral BMD, than non-hormone users. Postmenopausal status, late menarche, and bilateral oophorectomy were risk factors for low BMD. Protective factors against low BMD were increased body weight, increased number of pregnancies, as well as hysterectomy without bilateral oophorectomy. The majority (43.8%) of these operations had been performed due to the presence of leiomyomas. No significant correlation was found between nulliparity, breast-feeding or amenorrhea before the age of 30 and BMD. In the multiple regression analysis, gynecological variables could account for only 18.4-26.8% of the variance in BMD, while time since last periods, age, age at menarche, weight and hysterectomy were the most significant variables. We conclude that reproductive history gives rise to some special risk groups, to whom BMD measurements and osteoporosis prevention efforts should be directed. However, it is impossible to predict BMD by gynecological characteristics.

Exposure of an infant to cervical human papillomavirus infection of the mother is common

OBJECTIVE The purpose of this study was to determine the potential of exposure of an infant to cervical human papillomavirus infection of the mother. STUDY DESIGN Cervical scrapes of the mothers and nasopharyngeal aspirate fluids of their infants were analyzed at the time of delivery. The study included 106 infants born by vaginal delivery or by cesarean section and their 105 mothers. Positive results were confirmed and typed by direct deoxyribonucleic acid sequencing or single-strand conformation polymorphism of the polymerase chain reaction product. RESULTS Both the mothers and her infants samples were positive for the same type of human papillomavirus in 29 mother-infant pairs. Interestingly, five infants born by cesarean section were found to be human papillomavirus deoxyribonucleic acid positive for the same human papillomavirus type as their mother. The overall concordance between human papillomavirus types in the mother and her newborn was 69% (29/42). Regardless of match in types found in the mothers and her infants sample, human papillomavirus deoxyribonucleic acid positivity was found in 39 of all the 106 infants (37%). CONCLUSIONS Our results indicate that the infant of the human papillomavirus-infected mother is exposed to infection even when the cervical infection of the mother is subclinical. The possibility of transplacental exposure has to be considered as well.

Versican in epithelial ovarian cancer: Relation to hyaluronan, clinicopathologic factors and prognosis

Versican, a proteoglycan previously reported to increase in other malignant tumours, was studied immunohistochemically in 299 primary epithelial ovarian cancers, their 43 metastases and 6 normal ovaries to evaluate its prognostic value and relation to hyaluronan, another extracellular matrix molecule increased in cancer and a binding partner of versican. The stainings were scored according to the area percentage of strong versican signal of total peri‐ and intratumoural stroma as low (<15%) or high (≥15%). Epithelial staining of the tumours was scored as positive or negative. Low and high area percentage of strong stromal versican staining were observed in 133 and 166 carcinomas, respectively. A low area percentage of strong stromal versican staining correlated with mucinous histology (p = 0.019) and early International Federation of Gynecologists and Obstetritians (FIGO) stage (p < 0.0005), whereas a high percentage was associated with reduced 5‐year survival rate of the patients (44% vs. 32%; p = 0.032). Versican was associated with the cancer cells in 151 tumours and correlated with clear cell histology (p < 0.0005), early FIGO stage (p = 0.049) and increased recurrence‐free survival (63% vs. 47%; p = 0.032). However, in Coxs multivariate analyses with the conventional prognostic factors included, neither stromal nor cancer cell‐associated versican reached a significant prognostic value. Versican is thus enriched in the malignant stroma surrounding and promoting the growth of ovarian cancer, probably acting with hyaluronan, and associates with unfavourable prognosis but does not constitute an independent indicator of patient survival.