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Premature ovarian failure (POF) generally describes a syndrome consisting of amenorrhea, sex steroid deficiency, and elevated/menopausal levels of ganadotropins in a woman aged more than two standard deviations below the mean age at menopause estimated for the reference population. Numerous questions relating to this condition remain unanswered, and several important management issues are yet to be addressed. The challenges posed by this important condition range from difficulties with nomenclature to the absence of standardized diagnostic criteria and management guidelines. In the present paper we discuss the management of spontaneous premature ovarian failure, highlight the challenging issues, review the current literature and propose a practical management outline based on our local practice. Women with POF have unique needs that require special attention. There is an urgent need for a more suitable terminology and evidence-based guidelines on which to establish the diagnosis and manage this difficult condition.

Secondary amenorrhea in women with normal estrogen levels increases the risk of endometrial carcinoma. Cyclical dydrogesterone induces regular withdrawal bleeding and effectively protects the endometrium of postmenopausal women receiving estrogens. In order to assess the efficacy of dydrogesterone in inducing regular withdrawal bleeds in premenopausal women with secondary amenorrhea or oligomenorrhea and normal estrogen levels, a double-blind, randomized, placebo-controlled, multicenter study was conducted in 104 women using cyclical dydrogesterone as is used for estrogen replacement therapy. Treatment consisted of dydrogesterone (10 mg/day on days 1-14 followed by placebo on days 15-28 of each cycle) given for six cycles of 28 days. The control group received placebo throughout the six cycles. Bleeding was documented by the patient on diary cards. The number of women with withdrawal bleeding during the first cycle was twice as high in the dydrogesterone group as in the placebo group (65.4% vs. 30.8%; p = 0.0004). Superiority of dydrogesterone was also observed for regularity of bleeding over the six cycles (p < 0.0001), although endometrial thickness after six cycles did not differ between the groups. In conclusion, dydrogesterone is significantly superior to placebo in inducing withdrawal bleeding, and maintaining regular bleeding, in women with secondary amenorrhea and normal estrogen levels.

The downturn in the use of hormone replacement therapy since the original publication of the Women's Health Initiative (2002) and Million Women studies (2003) has now stabilized. New products are now being developed which maintain benefits and minimise risks. However, some useful products have been withdrawn by Pharma companies through profitability decisions; other products will regrettably not be launched despite favorable data. New low- and ultra-low-dose oral preparations (containing 0.3 mg conjugated equine estrogens and 0.5 mg estradiol, respectively) appear to maintain benefits for symptom relief and osteoporosis whilst minimizing side-effects and risks. A 14 microg transdermal system appears to maintain bone protection without the need for endometrial protection. New progestogens can minimize progestogenic side-effects through antiandrogenic and antimineralocorticoid effects, e.g. drospirenone, bioidentical progesterone and selective progesterone receptor modulators. A new female androgen patch has been licensed in Europe for treatment of low libido causing distress (hypoactive sexual desire disorder) in surgically menopaused women on estrogen therapy. A non-hormonal option, desvenlafaxine succinate (a serotonin and noradrenaline reuptake inhibitor), for vasomotor symptoms is currently in phase-III clinical trial stage and should be launched in the next year. Additionally, a selective estrogen receptor modulator/conjugated equine estrogen preparation combination currently in phase-III clinical trials is showing encouraging data for efficacy/risks and should provide a further option for women using hormone therapy in the future.

There is a growing body of scientific evidence that complementary therapies such as isoflavone containing phytoestrogens might help menopausal symptoms. Women are now using them, believing them to be safer and "more natural" especially following the current controversies regarding HRT. However, the choice of treatments is confusing and with some preparations, little is known about their active ingredients, safety or side effects or how they may interact with other therapies. This paper examines the available evidence for management of menopause symptoms with isoflavone containing phytoestrogens, both in terms of efficacy and safety. An algorithm is suggested to demonstrate how these preparations may be integrated with conventional therapies to effectively manage menopause symptoms.

Objective: To evaluate the efficacy of two ultra-low-dose 17beta-estradiol plus norethisterone acetate (NETA) treatment regimens for relieving menopausal symptoms., Design: A total of 577 postmenopausal women were enrolled, in three treatment groups in a double-blind, randomized, placebo-controlled study of 0.5 mg 17beta-estradiol + 0.1 mg NETA or 0.5 mg 17beta-estradiol + 0.25 mg NETA or placebo. Participants returned at weeks 4, 8, 12 and 24 for climacteric complaint evaluation based on a daily diary vasomotor symptom record. Patients were assessed by the Greene Climacteric Scale and urogenital symptoms were also evaluated., Results: Treatment with ultra-low-dose 0.5 mg 17beta-estradiol + 0.1 mg NETA (0.1 Group) or 0.5 mg 17beta-estradiol + 0.25 mg NETA (0.25 Group) effectively reduced the severity and number of hot flushes within the initial weeks of therapy. Compared to placebo, a rapid, statistically significant decrease in the frequency and severity of hot flushes was achieved by week 3, followed by further improvement which continued throughout the study. There were no statistically significant differences between the active treatment arms., Conclusions: The data show that both ultra-low-dose regimens are effective in reducing the severity and number of hot flushes compared to placebo, with good safety profiles.

Objectives: To identify and describe current women's thoughts about the menopause, hormone treatment (HT) and perceptions about breast cancer., Methods: Between December 2004 and January 2005, 4201 postmenopausal women in seven European countries were interviewed via a standardized computer-aided telephone interview protocol., Results: Almost all women reported to have experienced climacteric symptoms, and 63% of the women rated them as being severe. Only 52% of women were aware of the benefits of HT for relief of climacteric symptoms. Although 84% felt that severe symptoms should be treated, only 40% had used HT at some point in time. Thirty-four percent of the women preferring treatment with natural products did so because of the risk of breast cancer associated with HT. HT was recognized by 59% of the women as one of the most important contributors to an increased breast cancer risk. Most women received their information about HT and breast cancer risk from the media., Conclusions: This European survey reveals that the majority of women experience climacteric symptoms but that their decision whether or not to use HT is highly dependent on their concern about breast cancer risk. An increase in knowledge of the benefits and risks of HT is required for women to make appropriate decisions about hormone use.

Vasomotor symptoms are the most common menopausal symptom experienced by women and the leading reason menopausal women seek health care advice. The recent shift towards a more conservative use of hormone therapy (HT) during menopause has prompted the need for treatment regimens to be individualized according to symptom severity. Our objective was to develop a new algorithm that enables practitioners to customize treatment regimens according to symptom severity. In order to develop a comprehensive treatment algorithm, we conducted a literature review and considered the findings from recently published treatment guidelines from around the world. We also evaluated the results of systematic reviews investigating the efficacy and safety of complementary and alternative medicines. We found a growing trend away from prescription HT in women with mild to moderate symptoms and an increasing trend toward lifestyle modification and the use of complementary and alternative medicines. On the basis of these findings, we have developed an algorithm that accounts for symptom severity. The algorithm presented here provides treatment options based on symptom severity and a comprehensive approach for integrating lifestyle modifications and complementary therapies with prescription treatment regimens.

The biological plausibility for the effect of sex hormones on the central nervous system is now supported by a considerable amount of clinical data. This critical review guides the reader through the plethora of data, from the earliest reports of menstrual madness in the nineteenth century to neurobiological work in the new millennium. It illustrates through the scientific evidence base that, although the effect of estrogen on the central nervous system, particularly on mood and depression, remains a controversial area, there is now considerable evidence for the psychotherapeutic benefits of estrogens in the triad of hormone-responsive depressive disorders: postnatal depression, premenstrual depression and perimenopausal depression. The article also reviews the compelling data that testosterone supplementation has positive effects for depression, libido and energy, particularly where patients have only partially responded to estrogen therapy.

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.

Objectives: 1. To compare the effects of 25 mg and 50 mg oestradiol implants on serum follicle stimulating hormone and oestradiol levels; and 2. to assess the relationship of the dose of oestradiol implant and serum oestradiol on the effectiveness and duration of climacteric symptom control., Design: Randomised, double-blind investigation., Participants: Forty-four women, who had undergone total abdominal hysterectomy and bilateral salpingo-oophorectomy., Methods: The women were randomised to receive either 25 mg (n = 20) or 50 mg (n = 24) oestradiol implants. Follow up consisted of prospective symptom enquiry and hormone assays., Main Outcome Measures: Primary: climacteric symptom control: duration and effectiveness; secondary: serum oestradiol and follicle stimulating hormone levels., Results: Serum oestradiol was significantly higher and serum follicle stimulating hormone significantly lower after the fourth month of treatment in women receiving 50 mg implants. No significant difference in symptom control was noted in the two groups. The mean duration of symptom control was similar in the two groups: 5.9 months (SD 2.4) in those receiving 50 mg oestradiol and 5.6 months (SD 2.3) in those receiving 25 mg., Conclusion: The higher level, 50 mg oestradiol implants does not result in better control of symptoms nor in longer periods of symptom control compared with 25 mg oestradiol implants. In order to maximise compliance, 25 mg oestradiol implants should therefore be the treatment of choice for women with normal bone density seeking relief of climacteric symptoms.

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 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.

It is vital that we maximize compliance if patients are to receive the full benefits from hormone replacement therapy (HRT). One of the main factors for reduced compliance is that of progestogen intolerance. Progestogens have a variety of effects apart from the one for which their use was intended, that of secretory transformation of the endometrium. Endometrial effects vary between individuals and between different progestogens, leading to bleeding problems. Symptoms of fluid retention are produced by the sodium-retaining effect on the renin-aldosterone system. The nor-testosterone-derived progestogens can have adverse effects on skin, lipids, vasculature and insulin resistance. Negative mood effects are produced by most progestogens due to the effect on neurotransmitters via central nervous system progesterone receptors. Manipulation of the dosage and duration of progestogen, continuous administration of a low dose of progestogen and a reduction in the number of progestogenic episodes can be used to improve compliance. The progestogen and progesterone releasing coils and vaginal progesterone gel minimize systemic side effects and bleeding. Adverse effects can also be avoided by making use of the progesterone receptor-specific progestogens such as the pregnanes (e.g. cyproterone), nor-pregnanes (e.g. nomegestrol) and progesterone itself. Hysterectomy remains an option for the severely progestogen-intolerant woman. In the future, progestogen intolerance may not be an issue if selective oestrogen receptor modulators provide a complete alternative to HRT.

Hormone replacement therapy (HRT) is perhaps the most important development in preventive medicine in the Western world for half a century, yet long-term compliance is notoriously poor. Up to 75% of women who start on HRT are reported to drop out within the first 6 months. Poor compliance may arise from a lack of awareness of the benefits of HRT, or from a number of common misconceptions, particularly the idea that HRT is ¿unnatural', and will cause weight gain, cancer, or unpleasant side effects. While side effects (usually progestogenic) may of course occur on HRT, they can usually be managed by a change in the regimen. Studies of the efficacy and safety of Menorest, an adhesive matrix transdermal system, used in combination with dydrogesterone for 12 days in each cycle, show it to be effective in relieving menopausal symptoms and increasing lumbar and spinal bone mass. Menorest was as effective and well-tolerated as a reference oral treatment (conjugated estrogens), and its twice weekly application may be considered to promote compliance.

The diagnosis and management of lower abdominal pain is difficult, particularly for the inexperienced accident and emergency (A&E) or surgical trainee. In women, potential gynaecological causes may further confuse the picture. We analysed the incidence, spectrum of presentation and immediate management of 322 women presenting consecutively to an inner city A&E department over a 6-month period with lower abdominal pain. A standard questionnaire relating to history, examination, immediate investigations and preliminary diagnosis was completed by the attending A&E doctor. The cause of abdominal pain, according to the A&E doctor's diagnosis, was gynaecological in 61%, gastroenterological in 23%, urological in 7% and non-specific in 9% of cases. Of the women, 39% (124/322) were referred to a duty specialist, of whom 86% (107/124) required admission for investigation and/or treatment. Women initially diagnosed as having pain of gynaecological origin formed the largest group of patients to be referred. In 69% (67/97) of these cases, the A&E doctor's initial diagnosis was confirmed by the gynaecologist. This study shows that pain of gynaecological origin was the largest single cause of lower abdominal pain in women presenting to our A&E department and that, in the majority of cases, these women needed to be referred to the duty gynaecologist for immediate treatment. Although overall diagnostic accuracy rate was relatively high, the management of potentially life-threatening gynaecological conditions such as ectopic pregnancy was poor. These results emphasise the need to improve in-service gynaecological training in A&E departments.