Anabolic effect of estrogen replacement on bone in postmenopausal women with osteoporosis: histomorphometric evidence in a longitudinal study.

It is well recognized that estrogen (E(2)) prevents postmenopausal bone loss by suppressing bone resorption. Despite evidence that E(2) may also stimulate bone formation in animals, an anabolic effect in humans is still controversial. To investigate this, we studied 22 older postmenopausal females, with a mean age of 65.4 yr and mean interval of 16.9 yr since menopause and low bone mineral density. Transcortical iliac bone biopsies were performed before and 6 yr after E(2) replacement therapy (ERT) [75 mg percutaneous E(2) replaced 6-monthly plus oral medroxy progesterone acetate (5 mg daily) for 10 days each calendar month]. The mean serum E(2) level after 6 yr of treatment was 1077 (range, 180-2568) pmol/L. Bone mineral density improved in every patient, with a median increase of 31.4% at the lumbar spine and 15.1% at the proximal femur. Bone histomorphometry showed an increase in cancellous bone volume from 10.75% to 17.31% (P < 0.001). The wall thickness after 6 yr of E(2) treatment was 38.30 micrometer compared with 31.20 micrometer before commencement of ERT (P < 0.0005), indicating net bone gain. This is the first report showing histological evidence for an increase in cancellous bone volume, together with an increase in wall thickness, in a longitudinal follow-up study of ERT in older postmenopausal women. Our results show that E(2) is capable of exerting an anabolic effect in women with osteoporosis, even when started well into the menopause.

Hysterectomy, ovarian failure, and depression.

The incidence of depressed mood is high in women before hysterectomy. This finding is usually the effect of prolonged heavy periods, chronic pelvic pain, and severe premenstrual syndrome that warrant the surgical treatment. The therapeutic effects of hysterectomy thus include both the cure of physical symptoms and improvement of mood. However, in women with preexisting psychiatric illness or predisposing personality problems, depressed mood may persist or occur with the stress of hysterectomy. Hysterectomy is commonly performed in the perimenopausal age but also results in a premature ovarian failure. Thus, ovarian hormone deficiency following hysterectomy may be responsible for the negative effect on mood. The cyclical nature of such hormone-related depressed states often remains unrecognized in the absence of menstruation; without routine endocrinologic monitoring the need for estrogen replacement following hysterectomy is often missed. Associated bilateral oophorectomy results in the depletion of endogenous androgens, which also has a significant effect on mood. Estrogen plus testosterone replacement following hysterectomy with or without bilateral oophorectomy has been shown to reduce the incidence of depressed state. The compliance with hormone replacement following hysterectomy is high in the absence of withdrawal bleeding and the depressant effect of progestins on mood. Therefore, a practice of regular endocrinologic monitoring following hysterectomy to detect the need for estrogen replacement and a near-routine replacement of combined estrogen and testosterone following bilateral oophorectomy should be adopted to reduce the incidence of posthysterectomy depression.

Controlled ovarian hyperstimulation: an adjunct to assisted reproductive technology.

Controlled ovarian hyperstimulation was given to a study group consisting of male factor, endometriosis, and unexplained infertility. The aim of the study was to determine whether COH might be of value for such couples in a setting lacking ART facilities. When compared with their own spontaneous cycles or with a control group (untreated but scanned), COH proved significantly better for unexplained infertility. However, COH was not significantly effective for male factor infertility. This study shows that COH should be offered routinely in general hospitals to couples on long-term waiting lists for ART (especially those facing enforced expectant management).

The role of transvaginal ultrasonography in pre-operative case selection and post-operative follow up of endometrial resection.

50 patients undergoing transcervical endometrial resection (TCRE) for abnormal uterine bleeding underwent transvaginal ultrasonography (TVUS) before danazol therapy, immediately pre-operatively, and 3 months post-operatively. There were no significant changes in the uterine dimensions but as expected the endometrium became thinner (p < 0.0005) after treatment with danazol facilitating endometrial resection. 12 cases (24%) continued to have menstrual problems. In those cases TVUS showed unchanged endometrium (4), minimum residual endometrium (5), irregular uterine cavity (5), and fibroids (2) as probable causes of failure. These findings guided the choice of further management as follows: conservative for minimum residual endometrium, repeat TCRE for unchanged endometrium, and hysterectomy for irregular uterine cavity and fibroids. The value of TVUS in diagnosing the cause of post-operative pain was limited to the cases (2) of haematometra. The smaller transverse (< 6 cm) and anteroposterior (AP) (< 4.5 cm) dimensions of the uterus (p < 0.05, < 0.05), a significant reduction in these dimensions after the operation (p < 0.0005, p < 0.01) along with the absence of endometrium (p < 0.0001), fibroids and irregular uterine cavity (p < 0.005) predicted a favourable outcome of TCRE. This study substantiates the role of TVUS in TCRE for proper selection of cases, determination of the causes of failure and their subsequent management, leading to an improved outcome.

Maternal and fetal plasma levels of markers of bone metabolism in gestational diabetic pregnancies.

The aim of this study is to determine whether gestational diabetes has any effect on maternal and fetal bone metabolism. We collected maternal and umbilical cord blood samples from 19 women with gestational diabetes and 19 controls at the time of delivery. The plasma levels of carboxy terminal pro-peptide of type I pro-collagen (PICP) and cross-linked carboxyterminal telopeptide of type I collagen (ICTP) were used to monitor the rate of bone formation and degradation respectively. There is a significant correlation between the 1 hour postprandial blood glucose and the maternal levels of ICTP (r = 0.560, P = 0.004), but there was no significant difference in maternal or fetal levels of PICP and ICTP between the study and control groups (P = 0.411 maternal PICP, P = 0.241 maternal ICTP, P = 0.365 fetal PICP and P = 0.781 fetal ICTP). In the gestational diabetes group, there was a significant correlation between maternal and fetal ICTP (r = 0.694, P = 0.001), but there was no correlation between maternal and fetal levels of PICP (r = 0.334, P = 0.175). Although the maternal levels of ICTP is related to the 1 hour postprandial blood glucose level, gestational diabetes does not affect the maternal or umbilical cord levels of the serum markers of bone metabolism.

The relationship of fetal serum markers of bone metabolism to gestational age.

The aim of this study is to determine the pattern of fetal bone metabolism by measuring umbilical cord levels of carboxy terminal pro-peptide of type I pro-collagen (PICP) and cross-linked carboxyterminal telopeptide of type I collagen (ICTP). PICP and ICTP directly monitors the rate of bone formation and resorption, respectively. Samples were obtained at the time of delivery from 20 healthy women with pregnancies at different gestations. There is a significant inverse correlation between fetal levels of PICP and ICTP, and gestation (PICP r=-0.504, p=0.023; ICTP r=-0.713, p < 0.001), and between ICTP and birth weight (r=-0.466, p=0.038), but the birth weight effect is a function of gestational age. Therefore, both bone formation and resorption decrease with gestational age. Although contrary to the suggestion that fetal ossification increases at the end of pregnancy, such changes may be due to the shift from growth to maintenance.

Patients' outlook, experience, and satisfaction with hysterectomy, bilateral oophorectomy, and subsequent continuation of hormone replacement therapy.

OBJECTIVE: Our purposes were to investigate patients' opinions of hysterectomy, bilateral oophorectomy, and hormone replacement therapy and to evaluate whether their outlook and experience influenced the overall satisfaction and continuation of hormone replacement therapy. STUDY DESIGN: We conducted a questionnaire survey of 200 patients before and 2 years after hysterectomy with or without bilateral oophorectomy. Postoperatively all patients received long-term estradiol and testosterone replacement. The inquiries of patients' views included (1) preoperative awareness of indication and outlook, (2) postoperative recovery, symptom relief, and experiences with hormone replacement therapy, (3) perceived benefits and problems, (4) changes in physical well-being, psychologic state, and sexual activity, (5) continuation of hormone replacement therapy, and (6) overall satisfaction. RESULTS: The outlook toward hysterectomy, bilateral oophorectomy, and hormone replacement therapy was positive in 77.4%, 87.1%, and 76.3%, respectively. The experience was positive in the majority, with a satisfactory postoperative recovery (70.6%), complete symptom relief (77.9%), and minimal side effects with hormone replacement therapy (5.2%). The benefits included improved physical well-being (79.9%), lower depressive symptoms (32.0%), and better sexuality (31.4%). The continuation rate of hormone replacement therapy was 97.4%, and overall satisfaction was positive in 88.7% of patients. The independent predictors of satisfaction were outlook toward hysterectomy and incomplete symptom relief. CONCLUSION: The outcome of hysterectomy, bilateral oophorectomy, and hormone replacement therapy was satisfactory to most patients.

The psychological outcome of hysterectomy.

The objective of this study is to review the published literature on psychological outcome of hysterectomy and oophorectomy for non-malignant indications. The relevant publications over the past 30 years until the end of 1997 were identified by a MEDLINE computer search. This was followed by hand searches of the relevant references in the literature identified by the electronic search. The published studies on the psychological outcome of hysterectomy have been selected to identify the incidence, possible causes and risk factors of psychological morbidity, and the measures that can be adopted to improve the outcome. The study showed that the majority of retrospective studies reported an adverse psychological outcome after hysterectomy. However, all prospective studies showed that the incidence of depressed mood is higher even before hysterectomy, owing to pre-existing psychiatric illness and personality and psychosocial problems, as a result of the emotional response to gynecological symptoms or as a manifestation of associated ovarian failure. Hence, the therapeutic effects of hysterectomy include improvement of mood in some but not all patients, unless proper case selection, psychiatric evaluation and preoperative counselling are arranged. An early detection of ovarian failure after hysterectomy, the initiation of hormone replacement therapy (HRT) immediately after surgery in perimenopausal women and in those undergoing oophorectomy, as well as regular follow-ups to ensure long-term compliance with HRT, would also improve the psychological outcome. In conclusion hysterectomy itself is not the cause of any adverse psychological outcome. Psychological symptoms actually improve in the majority of women, with the relief of distressing gynecological symptoms and the correction of ovarian hormone deficiency, but hysterectomy may not be of any benefit in women with prior psychiatric illness and those with personality and psychosocial problems.

Superovulation and timed intercourse: can it provide a reasonable alternative for those unable to afford assisted conception?

Superovulation was performed prospectively with pure follicle stimulating hormone (FSH) to a group of 224 infertile patients with ovulatory factor (51), male factor (60), mild/moderate endometriosis (24) and unexplained infertility (72). The aim was to produce three or four leading follicles in order to compensate for a 'deficient' factor. Ovulation was induced with human chorionic gonadotrophin (HCG) and monitoring was performed entirely by serial transvaginal ultrasound on alternate cycles up to a maximum of six cycles (1120 treatment cycles) with intervening cycles being used as self-controls (932 rest cycles). A further control group of 56 patients was matched for age, category and duration of infertility and was only scanned serially (336 control cycles). Seventy-four pregnancies were achieved and 54 delivered, giving a cumulative pregnancy rate per couple of 33% and a cumulative take home baby rate of 24% per couple after a maximum of six cycles of treatment. When compared with the rest or control cycles, treatment was significantly effective for ovulatory (P < 0.001), mild/moderate endometriosis (P < 0.01) and unexplained infertility (P < 0.01) but not for male infertility. Furthermore, pregnancy was five times more likely during the first four treatment cycles (P = 0.00006, odds ratio = 5) at the expense of a significant multiple pregnancy rate (18.9%) and mild/moderate ovarian hyperstimulation rate (12%). We conclude that four cycles of superovulation should be routinely offered to couples on waiting lists for assisted conception or to those unable to afford it, in anovulatory, mild/moderate endometriosis and unexplained infertility. These results need confirmation by a prospective multi-centre randomized study.

Postpartum bone mineral density following antenatal dexamethasone therapy.

The aim of this study was to determine whether the changes in bone metabolism, which we have demonstrated previously with antenatal dexamethasone therapy, are associated with a lower bone mineral density. We assessed bone mineral density in the proximal femur and lumbar spine using dual photon X-ray absorptiometry after delivery in 15 women who received dexamethasone therapy for fetal lung maturation, and in 30 women who did not have dexamethasone therapy in pregnancy. The absolute bone mineral density, T scores and Z scores at the proximal femur and lumbar spine were similar, and the median values of T and Z scores were positive in both groups. We conclude that antenatal dexamethasone therapy has no long term effect on bone mineral density.

Increased maternal bone formation in type I diabetic pregnancies.

There is evidence that infants of insulin-dependent diabetics have increased intrauterine bone resorption and reduced bone mineral content at birth. The aim of this study was to determine if type I diabetes is associated with abnormal maternal bone metabolism. We measured the circulating levels of carboxyterminal propeptide of type I procollagen (PICP) and cross-linked carboxyterminal telopeptide of type I collagen (ICTP) in the third trimester of pregnancy in samples obtained from 19 pregnant women with type I diabetes and 19 pregnant controls, to monitor the rate of bone formation and degradation, respectively. Diabetic control was considered to be good as the mean hemoglobin A(1) level was less than 8.5%. The circulating levels of PICP were significantly higher in pregnant women with insulin-dependent diabetes than in controls with uncomplicated pregnancy (median IDDM 147 microgram/liter, control 115 microgram/liter, P = 0.0014), but there was no significant difference in the circulating levels of ICTP between the two groups (median IDDM 4.6 microgram/liter, control 4.6 microgram/liter, P = 0.907). Therefore, our findings suggest that there is an increase in bone formation in pregnant women with type I diabetes which may be related to the increased amount of insulin administered and the improvement in diabetic control associated with pregnancy.

Oocyte donation in Turner's syndrome: an analysis of the factors affecting the outcome.

A total of 29 women with Turner's syndrome (19 monosomy and 10 mosaic) had 68 cycles of oocyte donation that included 29 cycles of initial attempt and 39 cycles of subsequent attempts. Oral oestradiol valerate was used either in a variable dose (42 cycles) or in a constant dose (26 cycles) regimen for the endometrial preparation which was monitored by pelvic ultrasonography. The embryos/zygotes were transferred either fresh (50 cycles) or after cryopreservation (18 cycles) into the Fallopian tube (41 cycles) and uterine cavity (27 cycles) as appropriate. There were 28 clinical pregnancies including two sets of triplets resulting in a pregnancy rate of 41.2% per treatment cycle and an implantation rate of 17.1% per embryo transferred. The recipient's age, chromosomal constitution or associated uterine or tubal anomaly had no influence on the treatment outcome. The implantation and pregnancy rates were higher in the subsequent than initial cycles (22.6 versus 9.99%, P < 0.05; 51.3 versus 27.6%, P < 0.05). An endometrial thickness of > or = 6.5 mm was an important predictor of pregnancy but the endometrial echo pattern failed to predict the outcome. Although the total dose of oestradiol before embryo transfer was higher in the pregnant cycles than the non-pregnant ones and its gradation (< 50 mg, 50-100 mg, < 100 mg) influenced the implantation (3.4, 17.5, 26.3% respectively, P < 0.05) and pregnancy rates (10, 42.2, 61.5% respectively, P < 0.05), the effect was indirect by altering the endometrial thickness. The number of oocytes fertilized affected the pregnancy rate irrespective of the number of embryos transferred. The implantation and pregnancy rates were higher when fresh rather than frozen-thawed embryos were transferred (20.3 versus 8.2%, P < 0.05; 48 versus 22.2%, P < 0.05) but the route of transfer was of no statistical importance. The overall miscarriage rate was higher (50%), and was related to the presence of hypoplastic or bicornuate uterus and to a low oocyte fertilization rate.

Anabolic effect of long-term estrogen replacement on bone collagen in elderly postmenopausal women with osteoporosis.

Estrogen has been shown to stimulate osteoblasts in cell culture and increase bone formation in animal models. Such an anabolic effect of estrogen replacement therapy (ERT) would be beneficial to postmenopausal women with osteoporosis. Hence, we assessed the total collagen content and collagen crosslink maturity in iliac crest bone biopsy from 18 such women before and after 6 years of higher-dose ERT. These results were compared with the serum estradiol level and bone mineral density (BMD). Total collagen content of both cortical and cancellous bone increased, showing a median (95% CI) percent change of 6.7 (0.3-14.2) and 25.6 (13.5-33.8), respectively. Increase in collagen synthesis was supported by a rise in intermediate crosslinks in both cortical and cancellous bone, and mature crosslinks in cortical bone only. At the same time, BMD showed a substantial rise both at the lumbar spine and proximal femur with a median (95% CI) percent change of 28.6 (19.8-37.3) and 14.5 (8.4-20.7), respectively. Serum estradiol and BMD results correlated with cortical bone collagen levels. Our results suggest that long-term higher-dose ERT has a therapeutic role due to its anabolic effect on bone in postmenopausal women with osteoporosis.

Antenatal corticosteroid therapy and risk of osteoporosis.

OBJECTIVE: To assess the risk of maternal osteoporosis associated with antenatal corticosteroid administration for neonatal respiratory distress syndrome prophylaxis. DESIGN: Prospective longitudinal study. SETTING: Maternity unit of Chelsea and Westminster Hospital, London. POPULATION: Fourteen pregnant women who received dexamethasone therapy for fetal lung maturation in anticipation of delivery before 34 completed weeks of gestation. METHODS: Blood samples were collected before dexamethasone administration, 24 hours and 48 hours after the course of dexamethasone, and within 24 hours of delivery. Serum levels of carboxy terminal pro-peptide of type I pro-collagen (PICP) were measured to monitor the rate of bone formation, and serum levels of cross-linked carboxy terminal telopeptide (ICTP) were measured as a marker of bone resorption. MAIN OUTCOME MEASURES: Changes in the markers of bone turnover following dexamethasone administration. RESULTS: Serum PICP levels dropped 24 hours after dexamethasone therapy (P = 0.001), but partially recovered by 48 hours (P = 0.014) to reach higher than pre-therapy levels at delivery (P = 0.044). Although there were no corresponding changes in the serum levels of ICTP after 24 and 48 hours of therapy, levels increased from pretherapy to delivery (P = 0.006). CONCLUSION: Antenatal corticosteroid therapy leads to a transient suppression of, followed by an increase in, bone formation without any significant alteration in the pattern of bone resorption expected during pregnancy.

The feto-placental unit stimulates the pregnancy-associated increase in maternal bone metabolism.

The aim of the study was to investigate role of the feto-placental unit in the pregnancy-induced increase in maternal bone metabolism. To achieve this, circulating concentrations of carboxy terminal pro-peptide of type I pro-collagen (PICP, a marker of bone formation) and cross-linked carboxy terminal telopeptide of type I collagen (ICTP, a marker of bone resorption) were measured in three groups of pregnant women. Group 1 comprised 12 women with singleton pregnancies; group 2, nine women with twin pregnancies; and group 3, 19 women with multifetal pregnancies (> or =3 fetuses) before and after selective fetal reduction to twin pregnancies. Blood samples were obtained at 10-12 weeks gestation (groups 1-3, pre-fetal reduction in group 3) and 4 weeks and 8 weeks later (groups 2 and 3). Before fetal reduction there was a significant correlation between the number of fetuses and the concentrations of both PICP and ICTP (r = 0.503 and P = 0.001 and r = 0.573 and P < 0.001 respectively). The circulating concentrations of PICP and ICTP were significantly higher in the pre-reduction multifetal pregnancies than in the twin pregnancies (P < 0.001 and P = 0.0013 respectively). The circulating concentrations of ICTP in multifetal pregnancies fell by 4 weeks after fetal reduction to those observed in control twins. Concentrations of PICP were unaltered after fetal reduction. Higher order multiple pregnancies had the greatest decline in ICTP concentrations. These data suggest that the increased bone turnover observed in the multifetal pregnancies is due to a factor derived from the feto-placental unit and that this factor acts primarily to stimulate bone resorption.