A guide to the treatment of depression in women by estrogens.

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.

Hysterectomy and bilateral oophorectomy for severe premenstrual syndrome.

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.

Premenstrual syndrome and the use of alternative therapies.

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.

Continuation of hormone replacement therapy after hysterectomy.

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.

Use of complementary therapies by women attending a specialist premenstrual syndrome clinic.

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.

Five-year changes in bone density, and their relationship to plasma estradiol and pretreatment bone density, in an older population of postmenopausal women using long-term estradiol implants.

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.

Low dose 25 mg oestradiol implants and 1 mg norethisterone as continuous combined hormone therapy: a prospective study.

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.

Hormone replacement therapy and malignant melanoma: to prescribe or not to prescribe?

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.

Prevalence of and satisfaction with complementary therapies and hormone replacement therapy in a specialist menopause clinic.

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.

Reduced bone mineral density in HIV-positive individuals.

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.

Urogenital prolapse and atrophy at menopause: a prevalence study.

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.

Comparison of the biochemical effects of testosterone and estrogen on bone markers in surgically menopausal women.

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.

Plasma leptin concentrations are increased in women with premenstrual syndrome.

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.

Fibroid embolisation: a technique not without significant complications.

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 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.

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.

A study to evaluate serum and urinary hormone levels following short and long term administration of two regimens of progesterone cream in postmenopausal women.

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.

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.

The treatment of severe premenstrual syndrome with goserelin with and without 'add-back' estrogen therapy: a placebo-controlled study.

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.