Best practice & research. Clinical endocrinology & metabolism最新文献

The menopause transition is usually a gradual process occurring over many years, caused by the cessation of ovarian reproductive function, resulting in the end of menstrual bleeding. In the peri-menopause, ovarian function and therefore the production of the hormones oestrogen, progesterone and testosterone can fluctuate greatly, leading to a wide variety of symptoms, affecting multiple organ systems. Menopause and the management of its associated symptoms can be very challenging for patients and clinicians alike and can negatively impact quality of life. The management options include lifestyle adjustment, talking therapies, dietary supplements as well as prescribed medications, including hormone replacement therapy. The UK’s average life expectancy for women is approximately 81 years. Therefore, women will now live up to a third of their life being either peri- or postmenopausal. Thus, understanding and treating, where possible, the symptoms of menopause is essential to reduce the burden associated with this physiological state.

Vasomotor symptoms (VMS) are characteristic of menopause experienced by over 75% of postmenopausal women with significant health and socioeconomic implications. Although the average duration of symptoms is seven years, 10% of women experience symptoms for more than a decade. Although menopausal hormone therapy (MHT) remains an efficacious and cost-effective treatment, its use may not be suitable in all women, such as those at an increased risk of breast cancer or gynaecological malignancy. The neurokinin B (NKB) signaling pathway, together with its intricate connection to the median preoptic nucleus (MnPO), has been postulated to provide integrated reproductive and thermoregulatory responses, with a central role in mediating postmenopausal VMS. This review describes the physiological hypothalamo-pituitary-ovary (HPO) axis, and subsequently the neuroendocrine changes that occur with menopause using evidence derived from animal and human studies. Finally, data from the latest clinical trials using novel therapeutic agents that antagonise NKB signaling are reviewed.

Women are living a significant portion of their adult lives in the post-reproductive phase, and many seek help for debilitating menopausal symptoms. Every individual’s experience of menopausal transition is unique. Adopting a holistic approach to managing the menopause using a combination of lifestyle, hormonal, and non-hormonal interventions is key to maximise the quality of life of affected women. However, many opt to use non hormonal options or have contraindications to using hormonal therapy. Studies have shown that several pharmacological non-hormonal medications such as SSRIs, SSRI/SNRIs, Gabapentin, and Pregabalin are effective for managing vasomotor symptoms as well as other menopausal symptoms. Their main side effects are dry mouth, nausea, constipation, reduced libido, and loss of appetite. Clonidine is the only non-hormonal drug which is licenced for control of vasomotor symptoms in the UK, but has several side effects including dizziness and sleep disturbance. Cognitive Behavioural Therapy is recommended as a treatment for anxiety, sleep problems and vasomotor symptoms related to menopausal transition. Evidence for clinical efficacy and safety of herbal remedies and alternative therapies remains weak. Studies with neurokinin receptor 3 antagonists on women with hot flushes have shown improvement in vasomotor symptoms and results of large-scale studies are awaited.

Defining, diagnosing and managing premenstrual disorders (PMDs) remains a challenge both for general practitioners and specialists. Yet these disorders are common and can have an enormous impact on women. PMDD (premenstrual dysphoric disorder), one severe form of PMD, has a functional impact similar to major depression yet remains under-recognised and poorly treated. The aim of this chapter is to give some clarity to this area, provide a framework for non-specialists to work towards, and to stress the importance of MDT care for severe PMDs, including PMDD.

Purpose

To summarise the dosing options, regimens, pharmacokinetics, risks and benefits of oestrogen-based therapies for the treatment of menopausal symptoms.

Methods

A review of the literature was undertaken using multiple databases. Randomised trials, observational studies, meta-analyses and review papers were included.

Results

Multiple systemic preparations of oestrogen exist and all appear comparable in terms of efficacy. They differ by pharmacokinetics and those preparations that avoid hepatic metabolism have a lower risk profile in general although their use can be limited by skin barriers or patient acceptability. All vaginal oestrogen treatments are comparable in efficacy and have not been associated with any health risks. Side-effects between all preparations differ.

Conclusions

With regards to oestrogen treatments there is not a one size fits all. Multiple treatments are available and a clinician’s role is to guide and help women make evidence based, unbiased and informed choices.

A continuous process of bone turnover is central to bone health and strength. If bone resorption exceeds bone formation, bone strength deteriorates with resultant fractures. Osteoporosis is defined by a fracture or bone mineral density. The lack of ovarian estrogen after menopause causes a significant loss in bone strength, placing women at higher risk of osteoporosis. The probability of future fractures can be calculated by identifying risk factors in all menopausal women. Preventive action starts with a bone-friendly lifestyle. The need for and type of interventive medication can best be determined by classifying fracture risk as low, high, or very high using a combination of fracture history, bone mineral density, 10-year fracture probability or country-specific values. As osteoporosis is an incurable disease, treatment should be seen as a lifelong strategy consisting of the correct sequencing of available bone-specific drugs and appropriate drug-free periods when applicable.

Androgens play a key biological role in libido and sexual arousal in women, and knowledge about their complex role in other systems remains ambiguous and incomplete. This narrative review examines the role of endogenous androgens in women’s health throughout the life span before focusing on evidence surrounding the use of androgen-based therapies to treat postmenopausal women. The role of testosterone as a therapeutic agent in women continues to attract controversy as approved preparations are rare, and use of off-label and compounded formulations is widespread. Despite this androgen therapy has been used for decades in oral, injectable, and transdermal formulations. Responses to androgen therapy have been demonstrated to improve aspects of female sexual dysfunction, notably hypoactive sexual desire disorder, in a dose related manner. Substantial research has also been conducted into the role of androgens in treating aspects of the genitourinary syndrome of menopause (GSM). Evidence for benefits beyond these is mixed and more research is required regarding long-term safety. However, It remains biologically plausible that androgens will be effective in treating hypoestrogenic symptoms related to menopause, either through direct physiological effects or following aromatization to estradiol throughout the body.

Menopausal women with an intact uterus choosing estrogens for menopausal symptom relief require a progestogen for endometrial protection. The aim of this systematic review was to evaluate the risks of endometrial hyperplasia resp. malignancy with different progestogens used in combined MHT. Overall, 84 RCTs were included. We found that 1) most studies were done with NETA, followed by MPA, MP and DYD and LNG, 2) most progestogens were only available as oral formulations, 3) the most frequently studied progestogens (oral MP, DYD, MPA, oral and transdermal NETA, transdermal LNG) were assessed in continuously as well as in sequentially combined MHT regimens, 4) FDA endometrial safety criteria were only fulfilled for some progestogen formulations, 5) most studies demonstrated endometrial protection for the progestogen dose and time period examined. However, 6) study quality varied which should be taken into account, when choosing a combined MHT, especially if off-label-use is chosen.

Women may experience changes in sexuality across menopause, because at this step in life hormone deficiency interacts with several determinants in a bio-psycho-social perspective. Healthcare providers should inform women about menopause impact on sexuality and be proactive during consultation in disclosing sexual concerns that would require a targeted assessment. Sexual symptoms become more frequent as women age, but they do not always translate into sexual dysfunction diagnosis, for which distress is required. It is important to recognize conditions that may increase the risk of dysfunctional response to menopause challenges in order to promote sexual longevity through counselling and specific management. In this review, we report key elements for a comprehensive assessment of sexual health around menopause, with a focus on genitourinary syndrome of menopause (GSM) and hypoactive sexual desire disorder (HSDD), representing well identified clinical conditions affecting sexuality at midlife and beyond. We also address the issue of contraception across the menopausal transition, highlighting risks and benefits, and possible implications on sexual function.