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Premenstrual depression, postnatal depression and climacteric depression are related to changes in ovarian hormone levels and can be effectively treated by hormones. It is unfortunate that psychiatrists have not accepted this form of treatment and this paper is an attempt to simplify this treatment, which should include transdermal estrogens, possibly testosterone and, if the woman has a uterus, also progestogen. A balance is often necessary between these three hormones. Transdermal estrogens in the appropriate dose will suppress ovulation and suppress the cyclical hormonal changes that produce premenstrual depression. Estrogens also have a mood-enhancing effect in postnatal depression and the depression in the transitional phase of the menopause. It is possible to add transdermal testosterone which will improve mood, energy and libido. The problem is the progestogen as these women are often progestogen-intolerant. Progestogen should be used in the lowest dose and for the shortest duration necessary to prevent endometrial hyperplasia or the return of premenstrual syndrome-type symptoms if the women are progestogen-intolerant. The use of estrogens for depression in these women does not exclude the use of antidepressants. Hormone-responsive depression cannot be diagnosed by measuring hormone levels but can only be diagnosed by a careful history relating depression to the menstrual cycle, pregnancies and the perimenopausal years. These appropriate questions should prevent the endocrine condition of premenstrual depression being misdiagnosed as bipolar disorder and the woman given inappropriate treatment.

Background: Premenstrual syndrome (PMS) is a chronic, poorly understood psycho-endocrine disorder severely affecting 5%; of women. Hormonal therapy which suppresses ovulation is the mainstay of medical treatment, but these interventions are rarely permanent. We evaluated the effectiveness and patient satisfaction with total abdominal hysterectomy/bilateral salpingo-oophorectomy (TAH/BSO) in PMS sufferers, and assessed the post-operative HRT continuation., Methods: All women undergoing TAH/BSO for severe PMS between January 1994 and April 2000 were interviewed and responses recorded by structured questionnaire., Results: Forty-seven women were interviewed. Median age was 42 years (interquartile range 39.8-46.6) at the time of surgery. They had suffered with PMS for a mean of 9.68 years (SD 6.8) and received treatment for a mean of 3.57 years (SD 2.0) prior to referral to a gynaecologist. Fifty-two percent were treated with estradiol patches and 48% with estradiol implants prior to TAH/BSO. Ninety-six percent of women were 'satisfied' or 'very satisfied' with TAH/BSO, and 93.6% declared complete resolution of their cyclical symptoms; 93.6% were continuing with HRT usually by implants of estradiol and testosterone for a mean duration of 3.8 years (SD 1.86) post-operatively., Conclusion: Despite few reports of TAH/BSO as a treatment for severe PMS, we have found surgery, coupled with appropriate HRT, to be an extremely effective and well-accepted permanent cure for PMS.

The aim of this study was to observe whether bone mineral density (BMD) improves over 5 years in older women using estradiol implants. A total of 18 women were selected who had commenced hormone replacement therapy (HRT) around the age of 60 years. The median age was 60.9 years (range 59.7-63.2 years). Each woman had a pretreatment bone scan and then received 6-monthly subcutaneous 50 mg estradiol implants. Twelve untreated women were also selected who had had bone scans at baseline and after 5 years. A comparison of the changes in BMD between treated and untreated women was made using the Wilcoxon rank-sum test. All changes at the hip and spine were statistically significant improvements from baseline in the estradiol-treated group. After 5 years of treatment, the estradiol-treated group had significantly improved bone mineral densities compared with the untreated group. At the spine, the plasma estradiol concentration is statistically significantly correlated with the 5-year increase in bone density (r = 0.717, p = 0.004). There was found to be an inverse relationship between the percentage increase in BMD over the 5-year period and initial bone density (r = -0.635, p < 0.005). Thus estrogen is seen to have the effect of improving bone density in older women over 5 years of treatment. The increase in vertebral bone density is most marked in those women with the highest plasma estradiol levels and the lowest pretreatment bone density.

Premenstrual syndrome is a collection of symptoms that may be encountered by up to 95% of the population, although it is estimated to affect 5% of women severely. The use of complementary and alternative therapies is high among this group, but does not seem to compromise conventional treatment. It has been established that complementary therapies are used by a large proportion of the developed world, but their efficacy and safety are not always proven. This is partly due to the difficulty of studying alternative practices and the cost, but also with respect to premenstrual syndrome, problems with defining the condition and specifying end points are encountered. The difficulties in evaluating unorthodox therapies are elucidated and the evidence base for nonprescribed treatments for premenstrual syndrome is presented. Overall these women are a neglected group for whom the evidence for conventional therapy is sparse and controversial. Since the majority of women self-diagnose and self-medicate, it is important that physicians have an understanding of the variety of interventions tried and their worth.

It is desirable that young women with primary ovarian failure achieve normal peak bone mass to reduce the subsequent risk of osteoporosis, and that there are management strategies to replace bone that is already lost. While estrogen (E2) is generally considered to prevent bone loss by suppressing bone resorption, it is now recognized that estrogen also exerts an anabolic effect on the human skeleton. In this study, we tested whether estrogen could increase bone mass in women with primary ovarian failure. We studied the mechanism underlying this by analyzing biochemical markers of bone turnover and iliac crest biopsy specimens obtained before and 3 years after E2 replacement. Twenty-one women with Turner's syndrome, aged 20-40 years, were studied. The T scores of bone mineral density at lumbar spine and proximal femur at baseline were -1.4 and -1.1, respectively. Hormone replacement was given as subcutaneous E2 implants (50 mg every 6 months) with oral medroxy progesterone. Serum E2 levels increased incrementally from 87.5 pM at baseline to 323, 506, 647, and 713 pM after 6 months and 1, 2, and 3 years of hormone replacement therapy (HRT), respectively. The bone mineral density at the lumbar spine and proximal femur increased after 3 years to T scores of -0.2 and -0.4, respectively. The cancellous bone volume increased significantly from 13.4% to 18.8%. There was a decrease in activation frequency, but the active formation period was increased by HRT. There was a significant increase in the wall thickness from 33.4 microm at baseline to 40.9 microm after 3 years of HRT, reflecting an increase in bone formed at individual remodeling units. Although there was an early increase in biochemical markers of bone formation, these declined thereafter. Our results show that estrogen is capable of exerting an anabolic effect in the skeleton of young women with Turner's syndrome and low bone mass.

Objectives: To assess long-term hormone replacement therapy (HRT) usage in women after hysterectomy and to assess the relationship between age and long-term use of HRT in these women. Problems and comments of those women responding to a questionnaire were evaluated., Material and Methods: A postal semistructured questionnaire survey was performed in a single gynecological practice. A total of 545 consecutive women who had undergone a hysterectomy for benign conditions between January 1986 and September 1997 were studied, the main outcome measure being continuing use of HRT., Results: There was a response rate of 83.1% to the questionnaire; 83% of all responders were taking HRT at the time of the survey. A continuation rate of 95.7% was found among women who had had a hysterectomy after 1994, and of 84.7% among those operated on in 1989 or before. Implants were used by 68%, transdermal patches by 17%, oral preparations by 11% and estradiol gel by 4%. Ten per cent of those not taking HRT at present indicated that they were likely to start again in the near future. No correlation was found between age and likelihood of HRT continuation. Fifty per cent of women responding to the questionnaire made further comments: 17.6% of these made specific positive comments regarding HRT, 16.7% reported weight gain, 9.7% suffered breast symptoms and 13.2% admitted concerns regarding breast cancer., Conclusions: A high HRT continuation rate of between 95.7% (women having had their hysterectomy less than 5 years ago) and 84.7% (women 10 or more years from their operation) can be achieved in the long term. Considering the high proportion having implant therapy, the use of testosterone as well as estradiol replacement may be a major factor in the greater adherence to HRT of this group.

In this study, we investigate the use of complementary therapies by women attending a specialist premenstrual syndrome (PMS) clinic in the UK. Data was collected via an anonymous questionnaire survey of 100 women attending the clinic. Results showed 91% of women had used at least one form of complementary therapy for the management of their premenstrual symptomatology although only 35% were current users. Over half (53%) felt that these therapies had been of some benefit. Prescribed medication for PMS was being used by 71% of women at the time of the questionnaire and 83% of these women were satisfied with the perceived success of conventional therapy. In conclusion, the vast majority of women attending a specialist PMS clinic in the UK have used complementary therapies to treat this chronic debilitating condition but few continue use long-term. Treatment may be instigated by the woman with advice from her informal support network and/or her physicians. However as use is so prevalent, but with few randomized controlled trials conducted to show their benefits or risks, it is important to improve awareness of these therapies, both in qualitative and quantitative terms. Satisfaction with prescribed medications did not appear to be influenced by complementary therapy use in this group of women.

The anxiety regarding no-bleed regimens is that breakthrough bleeding and endometrial hyperplasia may occur. We aimed to demonstrate that 25 mg oestradiol implants can be adequately opposed by a low dose of progestogen protecting against osteoporosis. Twenty-two patients were recruited to the study. The mean age was 62 years and body mass index of 26.5. Median oestradiol rose from 77 pmol/L at baseline to 275 pmol/L at one year. Median endometrial thickness remained unchanged at 4 mm and only two women withdrew with bleeding problems. There was one case of proliferative endometrium at one year--all others samples were either atrophic or secretory. Lumbar bone density (L2-L4) rose significantly from 0.939 to 0.992 g/cm2 (6%, P = 0.005) and the total femoral density rose from 0.872 to 0.890 g/cm2 (+2.1%). Bone formation markers increased significantly (serum type 1 procollagen C terminal peptide, P1CP = 112-114, P = 0.0376) and bone resorption fell (serum type 1 collagen C terminal telopeptide, 1CTP = 3.0-2.9, P = 0.2863). E25 implants and low dose progestogen appear to avoid endometrial hyperplasia and bleeding problems while increasing bone density.

The mean age of presentation of malignant melanoma in women is the early fifties, a time that may be concomitant with the onset of the menopause. As the lesion can often be successfully surgically excised, many women will enter the menopause disease-free but in need of treatment for their menopausal symptoms. Melanoma has traditionally been considered to be an estrogen receptor-positive tumor, whose prognosis is adversely affected by estrogen, whether during pregnancy or in association with the oral contraceptive pill or hormone replacement therapy (HRT). Recent evidence now refutes this. As most recurrences occur in the first 2 years following treatment, it may be prudent to defer HRT until this time. There is a particular paucity of information pertaining to HRT and melanoma, such that, at present, there appears to be no justification for withholding this potentially beneficial therapy from menopausal women who have undergone treatment for melanoma.

It is almost impossible to cover all the options available for the treatment of premenstrual syndrome and premenstrual dysphoric disorder. This article discusses the most common and relevant options.

A total of 105 HIV-positive patients underwent dual-energy X-ray absorbtiometry (DEXA) scan to assess bone mineral density (BMD). The prevalence of reduced BMD was found to be 71% and was higher in patients who had ever been treated with protease inhibitors (PI). Our results suggest a possible association between PI and reduced BMD, and further complicate the debate regarding when to commence treatment of HIV and with what agents to start.

Objective: To assess the usage of both conventional and complementary therapies by peri- and postmenopausal women for the treatment of menopausal symptoms., Method: A prospective questionnaire was completed by 200 consecutive patients attending a tertiary referral London-based specialist menopause clinic between September and December 1999., Results: The median age of responders was 53.5 years (interquartile range 49-59). In total 137 women (68.5%) had ever tried an alternative treatment for the relief of their menopausal symptoms. Of these women 66% were regular users and 62% were satisfied with the effects of treatment. Women younger than the median age were significantly more likely to have used complementary therapies than older women (p = 0.036). Of the 200 participants, 184 women (92%) were current users of conventional hormone replacement therapy (HRT), and 89% were satisfied with the effects that their current HRT regimen had on their menopausal symptoms. Age was not related to satisfaction with conventional or complementary medicines. General practitioners and hospital doctors accounted only for 17% and 9%, respectively, of the primary sources of information for complementary medicines., Conclusions: High rates of usage and satisfaction were found with both conventional and complementary treatments for the relief of menopausal symptoms in our unit. For many of the women, both types of medicine are taken concurrently. Both general practitioners and hospital doctors are poor primary sources of information on complementary therapies for menopausal women.

For 285 subjects referred to a menopause clinic data were prospectively collected on the time elapsed since the onset of menopause (menopausal age), sexual activity, dyspareunia, smoking, chronic cough and constipation. Prolapse and atrophy were sought on examination. FSH assay confirmed menopausal status. We found an anterior wall prolapse in 51% of the subjects, of which 6% were protruding beyond the introitus. Posterior wall prolapse was present in 27% and apical prolapse in 20%; none was protruding beyond the introitus. No trend was noted between prolapse and menopausal age. Atrophy was evident in 34% of the women, and this was related to menopausal age (P<0.001). Forty per cent of the sexually active women admitted to dyspareunia, of which 2/3 were superficial. This correlated with advancing menopausal age (P<0.02). In conclusion, genital prolapse was frequent in the population of postmenopausal women, predominantly cystocele, but the prevalence did not correlate with menopausal age.

Leptin is a metabolic regulator of the hypothalamic- pituitary-gonadal axis, and plays an important role in human reproduction. Its neuro-endocrine effects are mediated by interactions with receptors in the hypothalamus, where emotional drive is also controlled. We postulated that circulating leptin concentrations are increased in premenstrual syndrome (PMS), and that this may be associated with the psychological symptoms of the disease. We obtained fasting venous samples from 32 women with PMS and 28 women with asymptomatic menstrual cycles, matched for age, body mass index and menstrual cycle length. Leptin concentrations were measured by radioimmunoassay. Leptin concentrations increased significantly during the luteal phases of the menstrual cycles of the control and PMS groups as compared with the follicular phase, having excluded the 11 women with PMS and six controls found to be anovulatory on the basis of mid-luteal plasma progesterone concentrations from the analysis. A greater increase was observed in women with PMS than the controls (P: = 0.00006 and 0.003 respectively). Although leptin concentrations in the follicular and luteal phases were higher in PMS than the controls, the difference was only statistically significant between the follicular phases (P: = 0.001). There was no clear relationship between leptin and oestradiol or progesterone in this study. These findings suggest that leptin may play a role in the pathophysiology of the disease, and requires further evaluation.

Twenty-five women with a previous total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH BSO) were given estradiol 50 mg implants at baseline, followed at 16 weeks with the combination of estradiol 50 mg and testosterone 100 mg. Blood samples were taken at 8-weekly intervals over 32 weeks. Serum levels of estradiol, testosterone, sex hormone binding globulin (SHBG) and agents involved in skeletal growth (growth hormone (GH), insulin-like growth factor 1 (IGF-1), carboxy terminal pro-peptide of type 1 pro-collagen (PICP; a bone formation marker) and cross-linked carboxy terminal telopeptide (ICTP; a marker of bone resorption)) were measured. Serum PICP levels increased significantly after estradiol alone (p = 0.0032) but the addition of testosterone had no significant effects on bone markers GH and IGF-1. These biochemical changes confirm previous studies, which found that the addition of testosterone did not augment the effect of estradiol implants on bone mineral density. Although physiological hormone replacement therapy in oophorectomized women would include replacement of both estradiol and testosterone, this may not to be necessary for prevention of osteoporosis where adequate serum estradiol levels are reached.

Uterine artery embolisation is a new minimally invasive technique used for the treatment of fibroids. Twenty-one women underwent bilateral uterine artery embolisation at our unit, and we assessed the efficacy, morbidity and patient satisfaction with the procedure. Mixed outcomes were found. Reduction in fibroid volume measured by magnetic resonance imaging was impressive, and the majority of women felt their symptoms had improved. One woman achieved a full term pregnancy following the procedure. However, the procedure involved a significant inpatient stay, analgesia requirement, and a slower recovery time than anticipated. One woman died following overwhelming sepsis occurring 10 days after the procedure. Further studies are required to assess the role this technique may play in the management of uterine fibroids.

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.

Objective: To determine the pharmacokinetics of a progesterone cream following short and long term dermal administration., Design: Single-centre, randomised, multiple-dose, open-label study., Setting: Reproductive Medicine Trust, London., Population: Twenty-four healthy postmenopausal women aged between 40 and 65 years were recruited through an advertisement in a local newspaper., Methods: The women were randomly allocated to progesterone cream 40 mg daily or 20 mg, twice daily, for 42 days., Main Outcome Measures: The concentration of progesterone in the serum was measured on days 1 and 42 before the morning dose, and at 2, 4, 6, 12 and 24 hours after the morning dose. Serum follicle stimulating hormone, oestradiol, testosterone and urinary pregnanediol-3-glucuronide were also measured on days 1 and 42., Results: Three subjects dropped out before using the cream and two more dropped out after the first treatment leaving a reportable sample of 19 women. There was a rise in the mean progesterone concentration at each sampling time between days 1 and 42. There was evidence of a rise in pregnanediol-3-glucuronide over the course of the study. There was no change in follicle stimulating hormone, oestradiol or testosterone. There was no difference between the two regimens., Conclusions: Transdermal progesterone (40 mg) per day for 42 days causes a small increase in serum progesterone concentration, although there is wide variation. Whether such levels are of clinical benefit remains to be seen.

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.

Objectives: A 1-year, open-label, non-comparative study evaluated the long-term tolerability and acceptability of a new generation matrix patch in post menopausal women with estrogen deficiency., Methods: Menopausal women (224) from 37 centres in five European countries received OESCLIM 50 microg/d (17-beta estradiol) for 3 months, titrated if necessary to either 25 or 100 microg/d for a further 9 months. Patients received either a continuous or discontinuous estradiol regimen with concomitant sequential progestogen (except hysterectomised patients). Skin tolerability was assessed by patient diaries and questionnaires. Global tolerability, efficacy, laboratory parameters and global acceptability were also monitored., Results: Almost two-thirds of women did not experience any kind of skin reaction and only 4.3% of all applications (752/17,702) caused site reactions. Of these, the majority caused only slight or no discomfort (63.2%). Only 0.37% of total applications required patch removal; none required therapy. A low percentage of patients withdrew due to tolerability issues: 2.7% due to skin reactions; 7.5% due to hyperestrogenism. The mean number of hot flushes experienced by symptomatic women reduced by 91% from 4.0 at baseline to 0.4 after 2 months. Total cholesterol reduced by 3.9% and LDL cholesterol by 5.1%, with no increase in triglyceride levels. Investigators assessed treatment as effective in 96.8% of cases; well tolerated locally in 93.1% and well tolerated generally in 89.5%. At the end of this 1 year study, 79% of patients wished to continue therapy., Conclusion: OESCLIM is well tolerated locally and systemically in long-term therapy with a high proportion of patients wishing to continue therapy after 1 year.

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.

Background: Current evidence suggests that information and treatment offered to women post-hysterectomy to prevent osteoporosis are poor., Objectives: To pilot a general practice audit protocol, to assess its ability to identify hysterectomized women and to offer appropriate information on fracture prevention., Method: A pilot audit study was designed to assess advice offered to hysterectomized women aged 25-64 years. Data on ovarian status were evaluated. Women were recalled for counselling if there was no evidence of advice on fracture prevention and if they were not taking hormone replacement therapy (HRT). Change in HRT usage was used as the outcome measure to assess the impact of the audit., Results: Baseline data were collated for 5743 women. In 1456 (25%), both ovaries were removed and 4029 (70%) had one or both ovaries conserved; 258 (5%) had incomplete ovarian data. The average age at hysterectomy with both ovaries removed was 43.9 years, and with conservation of one or both ovaries was 40.5 years and 40.1 years, respectively. Some 2888 (50%) were ever-users of HRT (both ovaries removed 70%, one ovary removed 53%, both ovaries conserved 44%). A total of 2083 (36%) were known current users (both ovaries removed 53%, one ovary removed 40%, both ovaries conserved 30%). The mean duration of use in 2620 ever-users was 44 months. This was similar for all the women irrespective of ovarian status. Eighty per cent of those given HRT reported receiving some advice. Seventy-seven per cent of those not given HRT had not received advice. By the end of the audit, 424 had commenced HRT (20% increase). Current use rose to 44% (both ovaries removed 59%, one ovary conserved 46%, both ovaries conserved 39%). Sixty-three per cent of new users chose transdermal preparations., Conclusions: The mean age at hysterectomy of between 40.1 and 43.9 years indicates the potential for early ovarian failure. Use of HRT is associated with availability of counselling. Uptake was better than anticipated, but HRT usage was still well below optimum. This audit fulfills its objectives but not without cost implications. Year by year it should achieve significantly improved management and health of hysterectomized women, and improved standards of patient care.

The study aimed to determine if the addition of daily low-dose oral estrogen with a cyclical progestogen given to young women using a depot gonadotropin-releasing hormone (GnRH) analog implant for the treatment of their premenstrual syndrome (PMS) would affect the clinical outcome. In a double-blind placebo-controlled study in a specialist premenstrual syndrome clinic setting, 60 women aged between 20 and 45 years were randomized to one of three treatment groups: Group A (placebo implant four weekly + placebo tablets daily), Group B (goserelin 3.6 mg implant four weekly + estradiol valerate 2 mg daily with norethisterone 5 mg from days 21-28 of a 28-day cycle) or Group C (goserelin 3.6 mg implant four weekly + placebo tablets daily). Differences between PMS scores at 2, 4 and 6 months were compared with pretreatment values. There was a significant improvement in PMS scores in Group C (Zoladex + placebo) after 2, 4 and 6 months of treatment when compared to pretreatment values and Group A (placebo + placebo). The addition of a low-dose oral estrogen with a cyclical progestogen to GnRH analog treatment (Group B) resulted in a less dramatic response when compared to pretreatment values and no significant improvement when compared to Group A (placebo + placebo) at 2, 4 and 6 months of treatment. The addition of a low-dose oral estrogen with a cyclical progestogen to depot GnRH analog therapy in the treatment of PMS reduces the clinical response.

The effect of estrogens on the central nervous system, particularly mood and behavior, remains a controversial area which needs clarification, not just for understanding of depression in women but to ensure that such commonplace problems in women have efficient and appropriate therapy. There is now good evidence that estrogens are rapidly effective in the treatment of depression in many women but this information has not found its way through to those health care personnel, psychiatrists and psychologists who are principally involved in the treatment of depression. There is also strong evidence for the benefits of estrogens on cognitive functioning, not only in preventing the onset of dementia but also in improving the symptoms in the established condition. Recent work has also suggested a benefit for estrogens on mood in women diagnosed as suffering from chronic fatigue syndrome. This article reviews the effect of endogenous estrogen on the female central nervous system and the ever increasing evidence for the diverse psychotherapeutic effects of exogenous estrogens.

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.

Objective: To study the obstetric outcome of ovum donation pregnancies., Design: A retrospective analysis of 232 ovum donation pregnancies in the six years from 1988 to 1993., Setting: Infertility clinic in a private hospital., Participants: All ovum donation recipients that achieved pregnancy in the clinic during the stated time period., Main Outcome Measures: Percentages of live birth and miscarriages and ectopic pregnancies; number of sacs identified in the uterus at early (four weeks after transfer) and later scans; incidence of antepartum and postpartum haemorrhage; incidence of pregnancy-induced hypertension; incidence of preterm, low birthweight and small-for-gestational age babies; and incidence of operative deliveries., Results: Of 232 pregnancies, 151 babies were born (live birth rate of 20%); and 81 were lost (57 before eight weeks, 17 after eight weeks and seven ectopic pregnancies). In nine cases there were no intrauterine sacs at the early scan (two 'chemical pregnancies' and seven ectopic pregnancies). In 169 cases there was initially one intrauterine sac, ending with 102 singleton deliveries (60%); in 47 cases there were initially two intrauterine sacs, ending with 11 singleton deliveries (23%) and 32 twin deliveries (68%); in the seven cases where three sacs were identified initially, there were no singleton deliveries, three twin deliveries (one selective fetal reduction) and three triplet deliveries. Women with premature ovarian failures had a significantly higher pregnancy rate compared with those with functioning ovaries (P < 0.02). However, in the former group, the miscarriage rate was also significantly higher (P < 0.03) so that the number of term births was similar. The incidence of vaginal bleeding was 12% in the first trimester, 1.5% in the second trimester, and 2% in the third trimester. The incidence of postpartum haemorrhage was 12%. Thirty-two women had pregnancy-induced hypertension (23% of all deliveries). This occurred in 22/105 singletons (21%), 7/32 twins (22%) and in all three (100%) of the triplets. In the singleton group 13% of infants were preterm, 18% had a birthweight < 2.5 kg and 15% were < 3rd centile for birthweight at delivery (small-for-gestational age). Ovarian function was found to be the only factor that significantly influenced the incidence of small-for-gestational age babies (odds ratio 8.84; 95% confidence interval 1.1-70.0; P = 0.007). The overall operative delivery rate was 85% with the caesarean section rate being 69%., Conclusions: Women who become pregnant following oocyte donation should be considered obstetrically as high risk, especially those with ovarian failure because of the increased incidence of small-for-gestational age infants in these pregnancies. They are also at higher risk of pregnancy-induced hypertension and postpartum haemorrhage.

Background: Postnatal depression can have long-term adverse consequences for the mother, for the marital relationship, and for the infant's psychological development. Such depressions can be severe and resistant to both support and counselling and to therapy with antidepressant drugs. We investigated the antidepressant efficacy of oestrogen given transdermally., Methods: In a double-blind, placebo-controlled study, 61 women with major depression, which began within 3 months of childbirth and persisted for up to 18 months postnatally, were allocated randomly active treatment (n=34; 3 months of transdermal 17 beta-oestradiol 200 micrograms daily alone, then 3 months with added cyclical dydrogesterone 10mg daily for 12 days each month) or placebo (n=27; placebo patches and tablets according to the same regimen). The women were assessed monthly by self-ratings of depressive symptoms on the Edinburgh postnatal depression scale (EPDS) and by clinical psychiatric interview (schedule for affective disorders and schizophrenia [SADS]-change scale)., Findings: On pretreatment assessments the women in both groups were severely depressed (mean EPDS score 21.8 [SD 3.0] active group, 21.3 [2.9] placebo group; SADS scores, 66.3 [11.4] and 64.3 [10.7]). During the first month of therapy the women receiving oestrogen improved rapidly, and to a significantly greater extent than controls (mean EPDS scores 13.3 [SD 5.7] vs 16.5 [5.3]. Patients receiving placebo also improved over time but, on average, their scores did not fall below the screening threshold for major depression for at least 4 months. The estimated overall treatment effect of oestrogen on the EPDS was 4.38 points (95% Cl 1.89-6.87). None of a range of other factors (age, psychiatric, obstetric and gynaecological history, severity and duration of current episode of depression, and concurrent antidepressant medication), influenced the response to oestrogen., Interpretation: This study has shown that transdermal oestrogen is an effective treatment for postnatal depression. Further studies are required to establish the minimum effective dose and shortest necessary duration of treatment as well as the mechanism of antidepressant action of oestrogen.

Thirty-two (32) menopausal women were entered into the study (16 in each treatment group), of whom 24 completed the study. The objectives were to compare the long-term efficacy and the local and systemic tolerance of Menorest and Premarin in the control of menopausal symptoms, and the prevention of bone loss. After a 4-week treatment-free run-in period, patients were treated with continuous estrogen therapy (a twice weekly application with Menorest 50 or a daily oral administration of Premarin 0.625 mg) for one year. Patients were also given 20 mg oral Dydrogesterone per day for the last 12 days of each 28 day cycle of treatment. The main efficacy criterion was the reduction in the mean number of hot flushes per day at 12 months compared to baseline. This study was also considered as a pilot study to collect data on changes in the bone mineral density of the lumbar spine (L1-L4) assessments from baseline to week 30 and week 56. Menorest and Premarin were equally effective in the relief of menopausal symptoms over the 1-year period of treatment. The mean number of hot flushes per day decreased from 6.9 at baseline to 0.5 at 12 weeks and 0.1 at 12 months in the Menorest group, and from 7.0 to 0.3 and 0.0 in the Premarin group. Regarding the lumbar spine and hip densitometry results, Menorest prevented bone loss to the same extent as Premarin. This data confirms the positive action of estrogen, with oral in addition to transdermal administration on both trabecular and cortical BMD over 1 year of treatment. Tolerance was similar, with approximately the same number of patients with AEs, severe AEs and related to study drug AEs in both groups. There was one serious AE (breast carcinoma) diagnosed after 6-months of treatment. Chemotherapy and radiotherapy was initiated prior to surgery. According to the investigator it was not related to study drug and must have been present prior to study start. Menorest 50 and Premarin 0.625 were equally effective over the 1-year treatment period in reducing the mean number of hot flushes and the severity score of menopausal symptoms, including vasomotor, psychological and urogenital symptoms.

Two-hundred and fourteen (214) menopausal women with moderate to severe vasomotor symptoms, aged 40-65 years, were randomised. After a 4-week treatment-free period, each women received a continuous regimen of Menorest 50 twice weekly or Premarin 0.625 mg daily, for 12 weeks. Didrogesterone 10 mg was also given to all women for 12 days of every 28-day cycle. The objectives were to compare the efficacy and safety profiles of Menorest and an oral estrogen. A statistically significant reduction in the mean number of hot flushes occurred in each group compared to baseline with a decrease from 7.1 at baseline to 0.9 at 12 weeks in the Menorest group, and from 6.7 to 0.5 in the oral estrogen group; there was no statistically significant difference between the two groups (P = 0.36). With each successive treatment cycle, there was a continuous improvement in the number of hot flushes. The incidence and severity of menopausal symptoms were reduced in the same manner in both groups. There were no statistically significant differences in the mean plasma estradiol and estrone concentrations between the two treatment groups after 10 weeks of therapy. The mean estradiol to estrone ratio was similar in both groups, as was the number of adverse events observed. In summary, Menorest was as effective as an oral estrogen in alleviating menopausal symptoms.

Objective: To examine the long-term effects of hysterectomy with conservation of the ovaries on bone density of the lumbar spine and proximal femur., Methods: A cross-sectional study of the bone density of 40 postmenopausal women who had undergone hysterectomy with ovarian conservation before menopause compared with a matched group of 40 women who had not had hysterectomy. The 40 women who had undergone hysterectomy were also compared with a control population, using multiple linear regression analysis. Bone density of the femoral neck and lumbar spine was measured by quantitative digital radiography., Results: Bone density in the hysterectomy group was significantly reduced at the spine (P < .05) and at the femoral neck (P < .05) compared with the matched group. Comparisons of the hysterectomy group with the reference group demonstrated that in addition to significant reductions in bone density at the spine (P < .05) and hip (P < .05), bone density at the femoral neck (P < .05), trochanter (P < .05), Ward's triangle (P < .05), and the second (P < .05) and fourth (P < .05) lumbar vertebrae was also significantly less in the hysterectomy group., Conclusion: Premenopausal women who have hysterectomy will have significantly lower bone density than controls, despite conservation of both ovaries at the time of surgery.

Objective: To determine the efficacy of a 100 micrograms twice weekly dose of Estraderm TTS compared with a 200 micrograms dose in the treatment of severe PMS, and to determine the overall acceptability of the treatment. To determine the serum oestradiol levels produced by the two doses of Estraderm and to discover whether the lower dose suppresses ovulation., Design: Main: randomised, prospective, comparative study. Subsidiary: cross-sectional and prospective., Setting: Premenstrual syndrome clinic in teaching hospital., Subjects: Women with severe PMS confirmed by prospective daily symptom recording., Interventions: Estraderm TTS at a dose of either 100 or 200 micrograms twice weekly continuously with either dydrogesterone 10 mg or medroxyprogesterone acetate 5 mg, from day 17 to day 26 of each cycle., Main Outcome Measures: Main: change in total, exponentially smoothed, average maximum score (total-ESAmax) of 10 common premenstrual syndrome symptoms derived from Trigg's trend analysis and patient satisfaction. Subsidiary: plasma oestradiol and day 21 progesterone levels., Results: Main: no difference in change in total-ESAmax between Estraderm 100 micrograms and 200 micrograms groups. Greater drop-out rate and greater incidence of side effects attributed to oestrogen in higher dosage group. Satisfaction rate of 45% to 57% at eight months. Subsidiary: 1. Mean (95% CI) oestradiol level of 300 pmol/l (255 to 345) with Estraderm 100 micrograms and 573 (494 to 693) with Estraderm 200 micrograms; 2. Estraderm 100 micrograms suppresses mid-luteal progesterone from a mean (95% CI) of 35.5 (28.4 to 42.7) to 3.4 (2.4 to 4.5)., Conclusions: Estraderm TTS 100 micrograms twice weekly is as effective as 200 micrograms twice weekly in reducing symptom levels in severe premenstrual syndrome but is better tolerated. Estraderm 100 micrograms suppresses ovulation and results in a mean plasma oestradiol level similar to that observed in a spontaneous cycle.

Objective: To evaluate the effect of 75 mg oestradiol implants on the bone mass of older postmenopausal women with osteoporosis., Design: One year prospective-controlled study., Subjects: Thirty-two postmenopausal women over 60 years of age and more than five years postmenopausal with low bone density were recruited. Thirty women completed treatment for one year with 75 mg oestradiol implants. The changes in bone density were compared with a control group of 14 women. The side effects with treatment were documented., Main Outcome Measures: Dual energy X-ray absorptiometry of the lumbar spine and proximal femur using Hologic 1000 QDR before treatment and at one year. Plasma oestradiol assays were performed before and after one year., Results: The median percentage changes in the treated group after one year was 12.6% at the lumbar spine and 5.22% at the total hip. The increase in vertebral bone density was greatest in women with low initial bone density (r = -0.35, P < 0.05) and those with highest treatment plasma oestradiol levels (r = 0.47, P < 0.01). Side effects were common but most were transient and mild in nature., Conclusion: 75 mg oestradiol implants significantly increase the bone mineral density at the spine and hip of older postmenopausal women with established osteoporosis.

Objective: To investigate the attitude of consultant gynaecologists and general practitioners to various aspects of hormone replacement therapy and to compare the findings in these two groups., Design: Anonymous postal survey of 589 general practitioners and 998 consultant gynaecologists; 373 (63%) and 655 (66%) valid replies, respectively, were received., Main Outcome Measures: Views on universal treatment of eligible women, indications for hormone replacement therapy, prescribing practice, pretreatment investigation, monitoring, and contraindications to treatment., Results: More consultants (64%) than general practitioners (56%) thought hormone replacement therapy should be offered to all eligible women, with a significant trend against treatment amongst more senior consultants. Most practitioners were prepared to offer treatment before the cessation of menstruation, but only 27% of consultants and 11% of general practitioners recommended indefinite treatment. Most limited treatment to less than 10 years. Menopausal symptoms, premature natural and surgical menopause, and a family history of osteoporosis were regarded as indications for treatment, but less than half felt established osteoporosis an indication. Hormone replacement therapy was judged to reduce the risk of ischaemic heart disease and osteoporosis by both groups but there was less consensus on the prevention of cerebrovascular accident. In general, consultants had more faith in hormone replacement therapy as prophylaxis. One-quarter of consultants said that hormone replacement therapy should be initiated by consultants. Only 4% of general practitioners shared this view. About 30% of both groups required mammography, but less than 10% required sophisticated tests. A range of common cardiovascular conditions were regarded as contraindications, although general practitioners were more likely to regard thrombosis and cerebrovascular accident as contraindications. Breast cancer and a family history of breast cancer were regarded with suspicion by both groups., Conclusions: Practitioners were positively inclined to hormone replacement therapy, but many were unconvinced of its chronic use and use in those with cardiovascular conditions. There were differences in views as to who should initiate therapy.

Objective: To determine whether there is a dose-response effect of percutaneous oestradiol implants on the skeletons of postmenopausal women using a range of doses available in clinical practice., Design: One year randomised study., Subjects: Forty-five postmenopausal women who requested oestrogen replacement therapy were randomised to receive 25 mg, 50 mg, or 75 mg oestradiol implants. The bone mineral density changes were compared with a control group of 15 untreated women., Main Outcome Measures: Dual energy X-ray absorptiometry using Hologic 1000 QDR before treatment and after one year of treatment. Plasma oestradiol and follicle stimulating hormone levels before treatment and after one year., Results: There were significant correlations between the plasma oestradiol levels and the percentage increase in bone density at the lumbar spine, the total hip, the femoral neck, and the trochanter. The median (range) plasma oestradiol level was 327 pmol/l (114-853) in the 25 mg group, 358 pmol/l (220-957) in the 50 mg group and 518 pmol/l (167-828) in the 75 mg group. Three women who lost a significant amount of bone from the clinically relevant sites in the 25 mg oestradiol group all had plasma oestradiol levels below 300 pmol/l. None of the women in either the 50 mg or 75 mg oestradiol groups lost bone from these sites., Conclusions: Oestradiol implants resulted in a wide range of circulating oestradiol levels with each of the doses used. There was a significant relation between plasma oestradiol levels and the increases in bone density at both the lumbar spine and the proximal femur. None of the women lost bone density at the clinically important sites of the spine and femoral neck if their plasma oestradiol levels were above 300 pmol/l.

Objective: To identify the effects of percutaneous estradiol (E2) implants on bone histology and bone mass of postmenopausal women with low bone mineral density., Methods: Sixteen postmenopausal women with low bone mineral density were treated with 75-mg E2 implants. Each had iliac crest bone biopsies performed, following double-tetracycline labeling, before treatment and 1 year later. Dual energy x-ray absorptiometry of the lumbar spine and proximal hip was also performed before and after 1 year of therapy. Serum E2 and FSH were measured after 1 year., Results: There were significant reductions in the osteoid volume, osteoid surface, eroded surface, and activation frequency following treatment. There was a statistically insignificant increase in the median bone volume from 11.3 to 15.8%. The median percentage increase in bone density at the lumbar spine was 14.4% and at the total hip 5.3%. The median post-treatment serum E2 level was 570 pmol/L., Conclusions: Estradiol implants reduce bone turnover in the iliac crest without significantly increasing trabecular bone volume after 1 year. The increases in bone density at the spine and hip may be explained by increased mineralization within the existing trabecular bone. However, the iliac crest may not represent the effect of estrogen at sites susceptible to osteoporotic fracture. If resorption is suppressed more than formation, then new bone would be deposited to account for the increase in bone density.

It is common for women receiving oestrogen replacement therapy to experience adverse symptoms whilst taking cyclical progestogen. This study highlights the similarity of these symptoms to those experienced in pre-menstrual syndrome and confirms that the Moos Menstrual Distress Questionnaire is an appropriate tool for future research. The data also indicate that progestogens vary in the type of symptoms they cause. Norethisterone is more likely to cause symptoms from the Moos pain symptom cluster than either medroxyprogesterone or dydrogesterone, but is less likely to cause negative affect symptom cluster symptoms. The relative levels of oestrogen and progestogen may influence the severity of progestogenic symptoms.

In a retrospective study, the relationship between endometrial thickness and pregnancy rate has been studied in 59 ovum recipient women. Transvaginal ultrasound assessment of endometrial thickness was performed immediately prior to ovum transfer: 19 pregnant recipients had a mean endometrial thickness of 10.24 mm +/- 2.63 SD, 40 nonpregnant recipients had an endometrial thickness of 8.62 mm +/- 3.49 SD (t = 1.805, P = 0.0382). Only two pregnancies occurred in 15 recipients with an endometrial thickness < 7.5 mm, and none when the endometrial thickness was < 5 mm. Our results indicate that endometrial thickness is related to the functional receptivity of the endometrium.

Objective: To determine the effects of percutaneous estradiol (E2) implants on the collagen composition and maturity in the bone and skin of osteoporotic postmenopausal women., Methods: Sixteen postmenopausal women with low bone mineral density were treated for 1 year with 75-mg E2 implants. Iliac crest bone and skin biopsies were analyzed for collagen content and collagen cross-links before treatment and at 1 year. Dual energy x-ray absorptiometry of the lumbar spine and proximal femur was also performed before and after 1 year of therapy., Results: The cortical bone showed a significant increase in the mature cross-links of both hydroxylysylpyridinoline (P < .01) and lysylpyridinoline (P < .01), with a significant reduction in the percentage of collagen (P < .001). The pattern was similar in trabecular bone, with lysylpyridinoline increasing significantly (P < .05). The skin exhibited a significant reduction in the immature cross-link hydroxylysinonorleucine (P < .01), but no significant change in the percentage of collagen content or the mature cross-link histidinohydroxylysinonorleucine. The median increases in bone density were 11.5% at the spine and 4.34% at the total hip. The median post-treatment serum E2 level was 639 pmol/L., Conclusions: Bone mineral density increased at all the sites measured in the spine and proximal hip. The quality of the collagen within the transiliac biopsies had matured in that the concentration of the mature collagen cross-links had increased. These findings support a reduction in the turnover of bone collagen following estrogen replacement therapy. More important, the formation of a more mature collagen fiber should help to reduce the risk of future bone fracture.

Objective: To determine whether the lowest available dose of percutaneous implant, 25 mg estradiol (E2), is effective for the prevention of postmenopausal bone loss., Methods: Eighteen healthy postmenopausal women were treated with 25-mg percutaneous E2 implants for 1 year. Dual energy x-ray absorptiometry was performed at the lumbar spine and proximal hip using a quantitative digital radiography densitometer before treatment and after 1 year. Estradiol and FSH were also measured before and after 1 year of treatment. The changes in bone mineral density were compared with a matched reference group of 18 women who did not wish treatment., Results: The median percentage changes in the treated group after 1 year were 5.65% at the lumbar spine, 3.38% at the femoral neck, and 3.36% total hip. At 1 year, there was a significant increase in bone mineral density from baseline at all sites measured except Ward triangle. The median post-treatment E2 level was 320 pmol/L (range 114-813), and FSH was 28 IU/L (range 2-66)., Conclusion: This study demonstrates that 25-mg percutaneous E2 implants significantly increase bone mineral density at the spine and hip in postmenopausal women. This dose is effective to prevent postmenopausal bone loss.

This study was performed to evaluate the relative contribution of oocyte and uterine factors to the age-related reduction in fecundity. The pregnancy and miscarriage rates in women receiving donated oocytes were compared to those in women using their own oocytes in in-vitro fertilization (IVF) and gamete intra-Fallopian transfer (GIFT) procedures. Oocyte donation with embryo transfer was performed on 241 women in 371 cycles; 116 of these women became pregnant (48% per patient and 31.5% per cycle) of whom 40 (35%) miscarried, giving a live birth rate of 20.5%. Assisted conception, in the form of IVF/GIFT procedures, was performed on 1331 women using their own oocytes in 2194 cycles; 627 of these women became pregnant (47% per patient and 28.7% per cycle), of whom 228 (36%) miscarried, giving a live birth rate of 18.2%. Neither the age of the donor nor the age of the recipient was related to pregnancy rate. The age of the donor, however, was directly related to the miscarriage rate. On the other hand, the age of patients undergoing IVF/GIFT was inversely related to the pregnancy rate and directly related to the miscarriage rate. In women of 40 years or over, the overall pregnancy and live birth rates were significantly higher and the miscarriage rate was significantly lower in the group receiving donated oocytes compared to the group using their own oocytes. In summary, we suggest that the age-related decline in fecundity is associated with the age of the oocytes rather than the age of the uterus.

In view of the benefits of hormone replacement therapy (HRT) and the experience that only 10% of women maintain therapy, it is vital that all doctors are familiar with the pros and cons of HRT, so that women may be correctly advised. Here we discuss new issues and developments in HRT and current views on indications, complications and regimens of treatment.