Fourth consensus of the International Society for Premenstrual Disorders (ISPMD): auditable standards for diagnosis and management of premenstrual disorder.

Whilst professional bodies such as the Royal College and the American College of Obstetricians and Gynecologists have well-established standards for audit of management for most gynaecology disorders, such standards for premenstrual disorders (PMDs) have yet to be developed. The International Society of Premenstrual Disorders (ISPMD) has already published three consensus papers on PMDs covering areas that include definition, classification/quantification, clinical trial design and management (American College Obstetricians and Gynecologists 2011; Brown et al. in Cochrane Database Syst Rev 2:CD001396, 2009; Dickerson et al. in Am Fam Physician 67(8):1743-1752, 2003). In this fourth consensus of ISPMD, we aim to create a set of auditable standards for the clinical management of PMDs. All members of the original ISPMD consensus group were invited to submit one or more auditable standards to be eligible in the inclusion of the consensus. Ninety-five percent of members (18/19) responded with at least one auditable standard. A total of 66 auditable standards were received, which were returned to all group members who then ranked the standards in order of priority, before the results were collated. Proposed standards related to the diagnosis of PMDs identified the importance of obtaining an accurate history, that a symptom diary should be kept for 2 months prior to diagnosis and that symptom reporting demonstrates symptoms in the premenstrual phase of the menstrual cycle and relieved by menstruation. Regarding treatment, the most important standards were the use of selective serotonin reuptake inhibitors (SSRIs) as a first line treatment, an evidence-based approach to treatment and that SSRI side effects are properly explained to patients. A set of comprehensive standards to be used in the diagnosis and treatment of PMD has been established, for which PMD management can be audited against for standardised and improved care.

Clinical subtypes of core premenstrual disorders: a Delphi survey.

The purpose of this study was to classify the clinical subtypes of core premenstrual disorders during the International Society for Premenstrual Disorders' second consensus meeting. Multiple iterations were used to achieve consensus between a group of experts; these iterations included a two-generational Delphi technique that was preceded and followed by open group discussions. The first round was to generate a list of all potential clinical subtypes, which were subsequently prioritized using a Delphi methodology and then finalised in a final round of open discussion. On a six-point scale, 4 of the 12 potential clinical subtypes had a mean score of ≥5.0 following the second iteration and only 3 of the 4 still had a mean score of ≥5.0 after the third iteration. The final list consisted of these three subtypes and an additional subtype, which was introduced and agreed upon, in the final iteration. There is consensus amongst experts that core premenstrual disorder is divided into three symptom-based subtypes: predominantly physical, predominantly psychological and mixed. A proportion of psychological and mixed subtypes may meet the DSM-IV diagnostic criteria for premenstrual dysphoric disorder.

ISPMD consensus on the management of premenstrual disorders.

The second consensus meeting of the International Society for Premenstrual Disorders (ISPMD) took place in London during March 2011. The primary goal was to evaluate the published evidence and consider the expert opinions of the ISPMD members to reach a consensus on advice for the management of premenstrual disorders. Gynaecologists, psychiatrists, psychologists and pharmacologists each formally presented the evidence within their area of expertise; this was followed by an in-depth discussion leading to consensus recommendations. This article provides a comprehensive review of the outcomes from the meeting. The group discussed and agreed that careful diagnosis based on the recommendations and classification derived from the first ISPMD consensus conference is essential and should underlie the appropriate management strategy. Options for the management of premenstrual disorders fall under two broad categories, (a) those influencing central nervous activity, particularly the modulation of the neurotransmitter serotonin and (b) those that suppress ovulation. Psychotropic medication, such as selective serotonin reuptake inhibitors, probably acts by dampening the influence of sex steroids on the brain. Oral contraceptives, gonadotropin-releasing hormone agonists, danazol and estradiol all most likely function by ovulation suppression. The role of oophorectomy was also considered in this respect. Alternative therapies are also addressed, with, e.g. cognitive behavioural therapy, calcium supplements and Vitex agnus castus warranting further exploration.

Reproductive depression.

Reproductive depression is the depression in women that is related to the hormonal changes of the menstrual cycle, pregnancy and the menopause and is manifested clinically as premenstrual depression, postnatal depression and climacteric depression. These three components occur in the same vulnerable women in that a woman with depression in the menopausal transition will usually have a history of premenstrual syndrome (PMS; premenstrual dysphoric disorder [PMDD]), would have been in a good mood during pregnancy and then develop postnatal depression. When the periods return the depression becomes cyclical as PMS. These three conditions are effectively treated with transdermal estrogens which should be the first-choice therapy rather than antidepressants. Estrogens can be used together with antidepressants. The critical time to prevent long-term mood problems is the correct treatment of postnatal depression. In women with low energy and libido, often a side effect of antidepressants, the addition of transdermal testosterone is useful. These women with reproductive depression are often progesterone/progestogen intolerant and a smaller dose or duration of progestogen is a necessary compromise. Alternatively a Mirena IUS or rarely a hysterectomy is required.

Testosterone for low libido in postmenopausal women not taking estrogen.

BACKGROUND: The efficacy and safety of testosterone treatment for hypoactive sexual desire disorder in postmenopausal women not receiving estrogen therapy are unknown. METHODS: We conducted a double-blind, placebo-controlled, 52-week trial in which 814 women with hypoactive sexual desire disorder were randomly assigned to receive a patch delivering 150 or 300 microg of testosterone per day or placebo. Efficacy was measured to week 24; safety was evaluated over a period of 52 weeks, with a subgroup of participants followed for an additional year. The primary end point was the change from baseline to week 24 in the 4-week frequency of satisfying sexual episodes. RESULTS: At 24 weeks, the increase in the 4-week frequency of satisfying sexual episodes was significantly greater in the group receiving 300 microg of testosterone per day than in the placebo group (an increase of 2.1 episodes vs. 0.7, P<0.001) but not in the group receiving 150 microg per day (1.2 episodes, P=0.11). As compared with placebo, both doses of testosterone were associated with significant increases in desire (300 microg per day, P<0.001; 150 microg per day, P=0.04) and decreases in distress (300 microg per day, P<0.001; 150 microg per day, P=0.04). The rate of androgenic adverse events - primarily unwanted hair growth - was higher in the group receiving 300 microg of testosterone per day than in the placebo group (30.0% vs. 23.1%). Breast cancer was diagnosed in four women who received testosterone (as compared with none who received placebo); one of the four received the diagnosis in the first 4 months of the study period, and one, in retrospect, had symptoms before undergoing randomization. CONCLUSIONS: In postmenopausal women not receiving estrogen therapy, treatment with a patch delivering 300 microg of testosterone per day resulted in a modest but meaningful improvement in sexual function. The long-term effects of testosterone, including effects on the breast, remain uncertain. (ClinicalTrials.gov number, NCT00131495.)

Towards a consensus on diagnostic criteria, measurement and trial design of the premenstrual disorders: the ISPMD Montreal consensus.

Premenstrual disorders (PMD) are characterised by a cluster of somatic and psychological symptoms of varying severity that occur during the luteal phase of the menstrual cycle and resolve during menses (Freeman and Sondheimer, Prim Care Companion J Clin Psychiatry 5:30-39, 2003; Halbreich, Gynecol Endocrinol 19:320-334, 2004). Although PMD have been widely recognised for many decades, their precise cause is still unknown and there are no definitive, universally accepted diagnostic criteria. To consider this issue, an international multidisciplinary group of experts met at a face-to-face consensus meeting to review current definitions and diagnostic criteria for PMD. This was followed by extensive correspondence. The consensus group formally became established as the International Society for Premenstrual Disorders (ISPMD). The inaugural meeting of the ISPMD was held in Montreal in September 2008. The primary aim was to provide a unified approach for the diagnostic criteria of PMD, their quantification and guidelines on clinical trial design. This report summarises their recommendations. It is hoped that the criteria proposed here will inform discussions of the next edition of the World Health Organisation's International Classification of Diseases (ICD-11), and the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V) criteria that are currently under consideration. It is also hoped that the proposed definitions and guidelines could be used by all clinicians and investigators to provide a consistent approach to the diagnosis and treatment of PMD and to aid scientific and clinical research in this field.

A longitudinal study of the effect of subcutaneous estrogen replacement on bone in young women with Turner's syndrome.

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.

Premenstrual syndrome and premenstrual dysphoric disorder.

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.

Hormone therapy for reproductive depression in women.

An email survey of patients attending a PMS and Menopause Centre produced 238 patients whose principal presenting symptom was depression. Seventy-seven percent claimed to have had severe or moderate depression, 17% had had at least one psychotic episode and 14% had attempted suicide. Fifty-eight percent had seen a psychiatrist. Seventy-one percent had received antidepressants and 17% had received mood stabilising drugs. Twelve percent had been admitted to a psychiatric hospital and 3.8% had received electroconvulsive therapy. Sixty-eight percent had premenstrual syndrome as a teenager and 145 women (89%) out of 165 women who had been pregnant had no depression during pregnancy but 110 (66%) developed postnatal depression. Ninety-seven women (58%) who had been pregnant had suffered both premenstrual depression and postnatal depression. All were treated with transdermal estrogens and 93% also had transdermal testosterone. One hundred and seventy-one patients had a uterus and received cyclical progestogen to protect the endometrium and 63% of these developed the premenstrual syndrome-type symptoms of progesterone intolerance during the progestogen days. Thirty-five percent of patients claimed to be cured and 55% had a considerable improvement with estrogen therapy. Only 3.7% reported that there was no improvement. For 94%, the hormone therapy was a life-changing event for the better. None were worse. Forty patients had hysterectomy and bilateral oophorectomy for progesterone intolerance or heavy uterine bleeding and 38 replied that it was life changing for the better with less or no depression. It is concluded that premenstrual and postnatal depressions appear in the same vulnerable women. These women are typically well during pregnancy and are a sub group of reproductive depression which also develops climacteric depression in the transition phase. These types of depression are the product of hormonal changes and respond well to transdermal hormone therapy.

Treatment of premenstrual disorders by suppression of ovulation by transdermal estrogens.

The understanding of the cause and treatment of premenstrual disorders is confused but it is essentially the result of cyclical ovarian activity, usually ovulation, and an effective treatment should be by suppressing ovulation. This can be done by an oral contraceptive but as these women are progestogen intolerant the symptoms may persist becoming constant rather than cyclical. Alternatively, transdermal estradiol by patch, gel or implant effectively removes the cyclical hormonal changes, which produce the cyclical symptoms. A shortened seven-day course of a progestogen is required each month for endometrial protection but it can reproduce premenstrual syndrome-type symptoms in these women. Gonadotropin-releasing hormone with 'add-back' is effective in the short term. Laparoscopic hysterectomy and bilateral oophorectomy with adequate replacement of estrogen and testosterone should be considered in the severe cases with progestogenic side-effects.

Severe premenstrual syndrome and bipolar disorder: a tragic confusion.

Bipolar disorder and severe premenstrual syndrome (PMS) have many symptoms in common, but it is important to establish the correct diagnosis between a severe psychiatric disorder and an endocrine disorder appropriately treatable with hormones. The measurement of hormone levels is not helpful in making this distinction, as they are all premenopausal women with normal follicle-stimulating hormone and estradiol levels. The diagnosis of PMS should come from the history relating the occurrence of cyclical mood and behaviour changes with menstruation, the improvement during pregnancy, postnatal depression and the presence of runs of many good days a month and the somatic symptoms of mastalgia, bloating and headaches. Young women with severe PMS do not respond to the antidepressants and mood-stabilizing drugs typically used for bipolar disorder.

Ten reasons to be happy about hormone replacement therapy: a guide for patients.

In spite of the negative press reports following the 2002 Women's Health Initiative (WHI) publication, women can be reassured that in the correct circumstances, hormone replacement therapy (HRT) is beneficial and safe, particularly if treatment is started below the age of 60. Transdermal estradiol is probably safer than oral estrogens as coagulation factors are not induced in the liver and HRT is safer if a minimal duration and dose of progestogen is used. HRT is effective for the treatment of estrogen-deficiency symptoms of flushes, sweats and vaginal dryness. Estrogens prevent osteoporotic fractures and should be first-choice therapy, rather than bisphosphonates. Similarly, HRT protects the intervertebral discs in a way that non-hormonal preparations do not. Estrogens perhaps with the addition of testosterone help certain sorts of reproductive depression, as well as improving energy and libido. There is new evidence to support the previous observational studies that HRT reduces the incidence of heart attacks. Estrogen therapy has a beneficial effect upon collagen, thus improving the texture of the skin, the nails, the intervertebral discs and bone matrix. Discussion of side-effects should not be avoided, particularly the 1% extra lifetime risk of breast cancer. This should be balanced against the fewer heart attacks, fewer deaths and less osteoporotic fractures in those who start HRT below the age of 60.

Why are physicians reluctant to use estrogens for anything--or do they prefer 'PROFOX'?

The reluctance of physicians to use estrogens in women with hormone responsive disorders is a tragic result of the 2002 WHI study. Although their hostility to estrogen therapy antedated these studies, the flawed data is now used as justification for the denial of estrogens for treatment of low bone density and various types of hormone responsive depression in women. Estrogens should be first choice therapy for osteoporosis in women under the age of 60 years, but in practice bisphosphonates, with its increasing number of long-term side-effects, has become first-line therapy for physicians. These side-effects include osteonecrosis of the jaw, mid-shaft femoral fractures and the need for proton pump inhibitors, which further reduce bone density and add to the fracture risk. Psychiatrists fail to use transdermal estradiol for postnatal depression, premenstrual depression and perimenopausal depression in spite of randomized trials demonstrating their efficacy. Selective serotonin reuptake inhibitor therapy for depression independently decreases bone density and is also responsible for loss of libido, loss of mental acuity and dependence. Thus postmenopausal women with vasomotor symptoms, depression, loss of libido, vaginal dryness or low bone density are frequently denied effective estrogen therapy and given a combination of low-cost generic prozac and fosamax, which is in danger of becoming a post-WHI nightmare drug PROFOX (PROzacFOsamaX). This can only be avoided if advisory bodies review the reassuring evidence concerning estrogen therapy in women under the age of 60 years and advise accordingly.

Are oestrogens useful for the treatment of depression in women?

The relationship between mood changes and the menstrual cycle has been recognized for many years. Initial treatments involved removal of the ovaries to prevent fluctuation of oestradiol, but this was also associated with the long-term effects of hypo-oestrogenism such as osteoporosis or heart disease. More recently, the use of high-dose oestrogen has been explored with some success. A diagnosis of hormone-related depression is made on the history, where the problem is worse at a time of hormone fluctuation such as occurs in the premenstrual phase, in the postnatal period and in the years leading up to the menopause. Many women may only feel well for a minority of days in the month and the problem can become chronic. Antidepressant medication is not usually successful, although this is often the preferred treatment for general practitioners and psychiatrists, possibly because of the potential side-effects of high-dose oestrogen administration. This chapter covers the diagnosis and treatment of premenstrual depression, postnatal depression and depression occurring in the climacteric period to emphasize the chronic nature of the problem and the best ways of diagnosing and relieving this distressing condition.