Ospemifene and vulvovaginal atrophy: an update of the clinical profile for post-menopausal women.

INTRODUCTION: The demand for effective and safe treatments of genitourinary syndrome (GSM) in post-menopausal women (PMW) is growing. Published data on the efficacy and safety of ospemifene (OSP) prompt an updated literature review to enlighten possible improvements in the GSM treatment. AREA COVERED: We searched articles published in English from 2010 to 2023 through Medline (PubMed) and Embase databases with Boolean terms: OSP, PMW, GSM, endometrium, breast cancer, cardiometabolic syndrome, bone metabolism, adherence to treatment, and patient satisfaction. We selected randomized controlled trials (RCTs) and observational and cross-sectional studies and completed the search manually. EXPERT OPINION: Of the 157 retrieved records, 25 primary studies met the inclusion criteria (15 regarding efficacy and safety, two for additional effects, and four for adherence and satisfaction with the OSP treatment). Seven RCTs involved nearly 5,000 patients, 10 out of 18 prospective observational studies 563, and six retrospective analyses 356,439. Evidence of OSP treatment in PMW with GSM relies on RCTs and remarkable real-world data. The 25 primary studies showcased the high clinical response to symptoms, the favorable safety profile of OSP with very few adverse events, a neutral impact on the endometrium, breast, bone, and thrombosis, and the possible improvement of cardiovascular risk factors.

A pharmacoeconomic analysis from Italian guidelines for the management of prolactinomas.

Background: Prolactinoma, the most common pituitary adenoma, is usually treated with dopamine agonist (DA) therapy like cabergoline. Surgery is second-line therapy, and radiotherapy is used if surgical treatment fails or in relapsing macroprolactinoma. Objective: This study aimed to provide economic evidence for the management of prolactinoma in Italy, using a cost-of-illness and cost-utility analysis that considered various treatment options, including cabergoline, bromocriptine, temozolomide, radiation therapy, and surgical strategies. Methods: The researchers conducted a systematic literature review for each research question on scientific databases and surveyed a panel of experts for each therapeutic procedure's specific drivers that contributed to its total cost. Results: The average cost of the first year of treatment was €2,558.91 and €3,287.40 for subjects with microprolactinoma and macroprolactinoma, respectively. Follow-up costs from the second to the fifth year after initial treatment were €798.13 and €1,084.59 per year in both groups. Cabergoline had an adequate cost-utility profile, with an incremental cost-effectiveness ratio (ICER) of €3,201.15 compared to bromocriptine, based on a willingness-to-pay of €40,000 per quality-adjusted life year (QALY) in the reference economy. Endoscopic surgery was more cost-effective than cabergoline, with an ICER of €44,846.64. Considering a willingness-to-pay of €40,000/QALY, the baseline findings show cabergoline to have high cost utility and endoscopic surgery just a tad above that. Conclusions: Due to the favorable cost-utility profile and safety of surgical treatment, pituitary surgery should be considered more frequently as the initial therapeutic approach. This management choice could lead to better outcomes and an appropriate allocation of healthcare resources.

Alpha Lipoic Acid Efficacy in PCOS Treatment: What Is the Truth?

Polycystic ovary syndrome (PCOS) is among the most common female endocrinopathies, affecting about 4-25% of women of reproductive age. Women affected by PCOS have an increased risk of developing metabolic syndrome, type 2 diabetes mellitus, cardiovascular diseases, and endometrial cancer. Given the pivotal role of insulin resistance (IR) in the pathogenesis of PCOS, in the last years, many insulin-sensitizing factors have been proposed for PCOS treatment. The first insulin sensitizer recommended by evidence-based guidelines for the assessment and treatment of PCOS was metformin, but the burden of side effects is responsible for treatment discontinuation in many patients. Inositols have insulin-mimetic properties and contribute to decreasing postprandial blood glucose, acting by different pathways. ALA is a natural amphipathic compound with a very strong anti-inflammatory and antioxidant effect and a very noteworthy role in the improvement of insulin metabolic pathway. Given the multiple effects of ALA, a therapeutic strategy based on the synergy between inositols and ALA has been recently proposed by many groups with the aim of improving insulin resistance, reducing androgen levels, and ameliorating reproductive outcomes in PCOS patients. The purpose of this study is to review the existing literature and to evaluate the existing data showing the efficacy and the limitation of a treatment strategy based on this promising molecule. ALA is a valid therapeutic strategy applicable in the treatment of PCOS patients: Its multiple actions, including antinflammatory, antioxidant, and insulin-sensitizing, may be of utmost importance in the treatment of a very complex syndrome. Specifically, the combination of MYO plus ALA creates a synergistic effect that improves insulin resistance in PCOS patients, especially in obese/overweight patients with T2DM familiarity. Moreover, ALA treatment also exerts beneficial effects on endocrine patterns, especially if combined with MYO, improving menstrual regularity and ovulation rhythm. The purpose of our study is to review the existing literature and to evaluate the data showing the efficacy and the limitations of a treatment strategy based on this promising molecule.

Tibolone and Breast Tissue: a Review.

The safety profile of hormone replacement therapy (HRT) on breast is still controversial. Tibolone is an option of treatment for climacteric syndrome of postmenopausal women. Its risk profile on breast is debated. This is an updated narrative review focusing on the impact of tibolone on breast. Particularly, we will report data from major preclinical and clinical studies regarding the effects of the use of this compound on breast tissue and breast density. Moreover, we will analyze and discuss the most relevant findings of the principal studies evaluating the relationship between tibolone and breast cancer risk. Our purpose is making all clinicians who are particularly involved in women's health more aware of the effects of this compound on breast and, thus, more experienced in the management of menopausal symptoms with this drug. According to the available literature, tibolone seems to be characterized by an interesting safety profile on breast tissue.

Italian Guidelines for the Management of Prolactinomas.

INTRODUCTION: This guideline (GL) is aimed at providing a reference for the management of prolactin (PRL)-secreting pituitary adenoma in adults. However, pregnancy is not considered. METHODS: This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinologi (AME) has identified potentially relevant outcomes, which have then been rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" have been considered in the systematic review of evidence and only those classified as "critical" have been considered in the formulation of recommendations. RESULTS: The present GL provides recommendations regarding the role of pharmacological and neurosurgical treatment in the management of prolactinomas. We recommend cabergoline (Cab) vs. bromocriptine (Br) as the firstchoice pharmacological treatment to be employed at the minimal effective dose capable of achieving the regression of the clinical picture. We suggest that medication and surgery are offered as suitable alternative first-line treatments to patients with non-invasive PRL-secreting adenoma, regardless of size. We suggest Br as an alternative drug in patients who are intolerant to Cab and are not candidates for surgery. We recommend pituitary tumor resection in patients 1) without any significant neuro-ophthalmologic improvement within two weeks from the start of Cab, 2) who are resistant or do not tolerate Cab or other dopamine-agonist drugs (DA), 3) who escape from previous efficacy of DA, and 4) who are unwilling to undergo a chronic DA treatment. We recommend that patients with progressive disease notwithstanding previous tumor resection and ongoing DA should be managed by a multidisciplinary team with specific expertise in pituitary diseases using a multimodal approach that includes repeated surgery, radiotherapy, DA, and possibly, the use of temozolomide. CONCLUSION: The present GL is directed to endocrinologists, neurosurgeons, and gynecologists working in hospitals, in territorial services or private practice, and to general practitioners and patients.

Vasomotor symptoms and management of women undergoing treatment for breast cancer: literature review with focus on the therapeutic potential of cytoplasmic pollen extract.

OBJECTIVE: Effective management of vasomotor symptoms (VMS) in patients undergoing treatment for breast cancer (BC) represents a critical but frequent unmet need. This review summarizes the epidemiology, pathophysiology, and clinical features of VMS in patients with BC and provides a synopsis of the complementary and alternative medicine (CAM) approaches in relieving VMS with a focus on purified cytoplasm of pollen (PCP). METHODS: The literature on VMS epidemiology, pathophysiology, clinical burden, and CAM treatment in healthy women and patients with BC was reviewed. RESULTS: VMS are common in patients with BC undergoing hormonal treatment and negatively impact quality of life, leading to treatment discontinuation in up to 25% of patients with detrimental impact on risk of BC recurrence and overall survival. CAM approaches to treat VMS in patients with BC include vitamin E, phytoestrogens, and black cohosh, even if there is a lack of solid evidence to guide clinicians in the choice of treatment. PCP, obtained according to standards of good manufacturing practice, has a definite pharmacological mechanism of action, is devoid of estrogen activity, and has shown clinical efficacy on menopause-associated symptoms with a favorable safety profile and high compliance. As such, it appears to represent a valid management option to improve quality of life in patients with pre- and postmenopausal BC. CONCLUSIONS: Physicians should actively investigate the presence and impact of VMS in patients receiving therapy for BC. Additional and appropriately sized randomized clinical trials are needed to provide clear evidence on how to best meet the needs of patients with BC suffering from menopause-associated symptoms.

Subclinical hypothyroidism in women's health: from pre- to post-menopause.

OBJECTIVE: Subclinical hypothyroidism (SCH) is a quite frequent condition among women, affecting 3-12% of the general population. Its consequences on women's health in reproductive age, pregnancy and menopause have been extensively investigated but data about the effective impact of treatment with levothyroxine (LT4) remain conflicting. METHODS: This is a narrative review and analysis of the most relevant data until June 2021. RESULTS: SCH may affect reproduction. Evidence suggests that women with SCH undergoing assisted reproductive technique (ART) may benefit from LT4 therapy whereas there are no conclusive data regarding women attempting natural conception. SCH may be associated with several negative pregnancy outcomes, that is to say recurrent pregnancy loss (RPL), preterm delivery, preeclampsia and neurocognitive disturbances of offspring. However, the protective role of LT4 treatment has been established in selected cases, for instance in thyroid peroxidase antibody (TPOAb) -positive women with TSH greater than the pregnancy specific reference range and/or in TPOAb-negative women with TSH >10.0 mIU/L. In menopause, SCH can worsen the negative cardio-metabolic effects of hormonal loss and/or aging, by exacerbating dyslipidaemia and hypertension. Nevertheless, robust data about the benefits of LT4 therapy are still lacking and treatment should be encouraged with caution. CONCLUSIONS: SCH represents a challenging condition during pre- and post- menopause. An aware knowledge of its possible principal consequences could help all clinicians who are involved in women's health to manage more properly it, preventing its sequelae.

Vitamin D and Histological Features of Breast Cancer: Preliminary Data from an Observational Retrospective Italian Study.

Background: Vitamin D (vitD) may be involved in different extraskeletal conditions as well as skeletal muscle diseases. It has been hypothesized that, at least in part, a low level of vitD could contribute to facilitating cancer development. Breast cancer (BC) seems to be associated with low levels of vitD. Materials and methods: This was an observational retrospective evaluation of 87 women (mean age: 54 ± 12 years old) who underwent surgery for the treatment of BC. Our main purpose was to correlate the types of BC and the levels of vitD. Results: A positive significant correlation (R > 0.7) was found between non-invasive carcinoma in situ and 25(OH)D levels and age (R = 0.82, p < 0.05). A positive, but nonsignificant, correlation was reported between invasive ductal carcinoma and 25(OH)D and age (R = 0.45, p > 0.05). A negative but nonsignificant correlation was found between invasive lobular carcinoma and 25(OH)D and age (R = 0.24, p > 0.05). Discussion and Conclusions: We did not find a significant relationship between vitD and BC subtypes. Considering the positive significant correlation between vitD levels and age for in situ BC, although preliminary, our results seem to suggest a possible role of vitD in in situ BC. However, these findings need to be confirmed in larger studies.

The Role of Genetics, Epigenetics and Lifestyle in Polycystic Ovary Syndrome Development: the State of the Art.

Polycystic ovary syndrome (PCOS) is an endocrine-metabolic disease affecting about 20-25% of women in reproductive age. Different mechanisms could contribute to the development of its typical clinical features (i.e. hirsutism, acne, oligo-amenorrhea, alopecia). Some genetic and epigenetic aspects and lifestyle changes seem to be involved in PCOS development. In this review, we shall summarize data from principal studies evaluating the impact of major genetic, epigenetic and environmental factors on the appearance of this female disorder. Literature review and analysis of the most relevant data until May 2020. Current data suggest the importance of genetics and epigenetics in the appearance of PCOS. Several genes, including those related to adrenal and ovarian steroidogenesis as well as those associated with hormonal response to gonadotrophins, androgens and insulin, have been demonstrated to be associated with PCOS. Besides, the phenomenon of methylation of genes and the presence of specific microRNA (miRNA) could take part in PCOS aetiology. Intrauterine exposure to androgens, glucocorticoids and/or some stressful conditions for foetus could contribute to the development of PCOS and other disorders observed in adolescence and later (e.g. premature adrenarche, atypical puberty, metabolic syndrome). Emerging studies report a theoretical role of endocrine disruptors, intestinal dysbiosis and Advanced Glycation End products (AGEs) in PCOS. PCOS is a polygenic and multifactorial hormonal and metabolic dysfunction. An appropriate knowledge of personal and/or family history, lifestyle and nutritional habits of PCOS patients has a great importance to early identify and manage this syndrome.

The benefits of purified cytoplasm of pollen in reducing menopausal symptoms in peri- and post-menopause: an Italian multicenter prospective observational study.

BACKGROUND: Purified cytoplasm of pollen (PCP) is a non-hormonal herbal remedy used to manage vasomotor symptoms (VMS), sleep and mood disorders in menopausal women not relying on Hormone Replacement Therapy (HRT). Many studies demonstrated its efficacy and safety in post-menopause but few data are available about peri-menopause. METHODS: This is a multicenter prospective observational study on Italian symptomatic women in peri- and post-menopause referring to gynecology clinics of different areas of Italy, evaluating the effects of PCP therapy on hot flashes (HFs) and other parameters included in the Greene Climacteric Scale (GCS). RESULTS: We recruited 108 peri- and post-menopausal women (mean age 53.8±4 years), evaluating them at baseline (V0) and after 3 months of PCP treatment (V1). Basal median value of all items of GCS did not differ among all subjects. We found a significant improvement of HFs (P<0.0001) and night sweats (P<0.0001) between V0 and V1. Additionally, all items of GCS apart from loss of sensitivity to limbs (P=0.0746) significantly ameliorated after PCP therapy (P<0.05). CONCLUSIONS: According to these findings, PCP may be considered as an efficacious alternative non-hormonal treatment for the management of VMS as well as mood and sleep disturbances in both peri- and post-menopause.

Glucose/insulin metabolism and vitamin D in women with recurrent pregnancy loss.

OBJECTIVE: Glucose/insulin metabolism has been related to recurrent pregnancy loss (RPL) through mechanisms not really clarified. Also, vitamin D deficiency seems to be associated to RPL. The purpose of our study was to evaluate the correlation between glucose/insulin metabolism parameters and vitamin D levels in women with history of RPL. STUDY DESIGN: Observational retrospective study on RPL women. The correlation among vitamin D levels and fasting glucose (FG), fasting insulin (FI), Homeostatic model assessment of insulin resistance (HOMA-IR) index, area under glucose curve (AUC-Glyc) and area under insulin curve (AUC-Ins), was evaluated. RESULTS: One-hundred and twenty-seven RPL women were classified into three subgroups (0-1-2) according to the levels of FI. We found a statistically significant linear Pearson correlation between FI and HOMA-IR (r = .840; P = .001). An, inverse, but non-significant correlation both between vitamin D and FI (R = -.202, ns) and vitamin D levels and AUC-Ins (R = -.288, ns) was observed. The variables vitamin D, HOMA-IR and AUC-Ins were statistically significant in the considered subgroups (Vitamin D: ANOVA + Bonferroni test: 0 vs. 1; P = .001; 0 vs. 2; P = .010; 1 vs. 2; P = .657; HOMA-IR: ANOVA + Bonferroni test: 0 vs. 1; P = .014; 0 vs. 2; P = .001; 1 vs. 2; P = .001; AUC-Ins: ANOVA + Bonferroni test: 0 vs. 1; P = .010; 0 vs. 2; P = .206; 1 vs. 2; P = .980). CONCLUSIONS: Vitamin D might play additional roles in the pathogenesis of RPL, beyond its well known immunomodulatory role.

Clinical pharmacology of progestins.

INTRODUCTION: In this paper, we report general pharmacological profile and major biological activities of natural progesterone (P) and progestins. The aim of this article consists of synthesizing the principal aspects of pharmacology and metabolism of P and progestins related to the clinical consequences of their use. EVIDENCE ACQUISITION: We review scientific literature on the topic "progestins," evaluating the most relevant data from original articles, reviews, and meta-analyses. EVIDENCE SYNTHESIS: Progestins represent a specific class of synthetic analogues of P clinically employed (alone or associated with estrogens) to manage several gynecological conditions, for instance multiple abortions, luteal phase defect, premenstrual syndrome, abnormal uterine bleeding, endometriosis, and menopause (for hormone replacement therapy). Besides their use in the field of contraception, many non-contraceptive benefits of estroprogestins are mostly due to the activities of progestins. Pharmacological characteristics, dosage and individual metabolism could be listed among the principal aspects influencing their clinical effects. CONCLUSIONS: The choice of each progestin according to its pharmacological profile is crucial for the appropriate management of any gynecological condition. An aware knowledge of these compounds is fundamental to hone medical practice.

Bone metabolism in pregnancy and lactation.

INTRODUCTION: Different hormonal mechanisms regulate bone metabolism during pregnancy and lactation. In both those periods of life, a fine modulation of calcium metabolism is necessary to meet the needs of foetus and new-born. EVIDENCE ACQUISITION: We reviewed scientific literature on the topic "osteoporosis," "pregnancy" and "lactation," evaluating the most relevant data from original articles, reviews and meta-analyses. EVIDENCE SYNTHESIS: Pregnancy- and lactation-associated bone loss and related fractures rarely occur and, generally, clinicians must manage it case to case, since there is not a unique guideline. Fortunately, bone mineral density (BMD) usually tends to recover within 12 months after weaning, thus, it could be reasonable waiting of assessing the effective magnitude of bone mass regain before starting any pharmacological treatment. CONCLUSIONS: Osteoporosis and/or fragility fractures remain uncommon events associated with gestation and/or breastfeeding. The management of bone loss and/or fractures during those periods is generally conservative and a tailored approach is advisable in the absence of any specific recommendation in this field.

What women think about menopause: An Italian survey.

INTRODUCTION: Menopause is a critical period for most women who experience associated symptoms while they are still socially and individually active. OBJECTIVES: The objective of this study is to report how Italian women perceive and approach menopause. MATERIALS AND METHODS: A survey of 1028 Italian women aged 45-65 years was conducted by the Italian Center for Studies of Social Investments (CENSIS) through anonymous interviews using two methods: CATI (Computer Assisted Telephone Interviewing) and CAWI (Computer Assisted Web Interviewing). PRINCIPAL OUTCOME MEASURES: Principal outcome measures were women's perceptions and experiences of menopause and its treatments. RESULTS: The global consciousness and understanding of menopause was common (82.8 %) among Italian women and it was usually considered a physiological condition (77 %). Overall, 74.6 % of the sample were postmenopausal. Hot flushes were reported to be the most frequent (37.9 %) and bothersome symptoms (43.1 %) while 12.9 % of the women were asymptomatic. As for menopausal therapies, 24.5 % were on treatment; herbal medications were the most common remedy (63.3 %) whereas 7.6 % of the women took hormone replacement therapy (HRT). About half of the sample (50.4 %) had not sought help from the Italian National Health System (INHS). Medical expertise in the field of menopause was thought to be moderately satisfactory by 54.5 % of the sample. CONCLUSIONS: Italian women consider menopause a physiological condition. Most postmenopausal women had experienced symptoms but relied on non-hormonal treatments. The median women's satisfaction with the role of the INHS and medical competence suggests the need to improve current knowledge and awareness concerning menopause.

Calcium, vitamin D, vitamin K2, and magnesium supplementation and skeletal health.

Supplementation with calcium (Ca) and/or vitamin D (vitD) is key to the management of osteoporosis. Other supplements like vitamin K2 (VitK2) and magnesium (Mg) could contribute to the maintenance of skeletal health. This narrative review summarizes the most recent data on Ca, vitD, vitK2 and Mg supplementation and age-related bone and muscle loss. Ca supplementation alone is not recommended for fracture prevention in the general postmenopausal population. Patients at risk of fracture with insufficient dietary intake and absorption could benefit from calcium supplementation, but it needs to be customized, taking into account possible side-effects and degree of adherence. VitD supplementation is essential in patients at risk of fracture and/or vitD deficiency. VitK2 and Mg both appear to be involved in bone metabolism. Data suggest that VitK2 supplementation might improve bone quality and reduce fracture risk in osteoporotic patients, potentially enhancing the efficacy of Ca ± vitD. Mg deficiency could negatively influence bone and muscle health. However, data regarding the efficacy of vitK2 and Mg supplementation on bone are inconclusive.

Joint recommendations for the diagnosis and treatment of vulvo-vaginal atrophy in women in the peri- and post-menopausal phases from the Società Italiana per la Menopausa (SIM) and the Società Italiana della Terza Età (SIGiTE).

Herein, joint recommendations for diagnosis and treatment of vulvo-vaginal atrophy (VVA) in women in the peri- and post-menopausal phases from the Società Italiana per la Menopausa (SIM) and the Società Italiana della Terza Età (SIGiTE) are presented. The recommendations are aimed at all healthcare personnel caring for women in the menopausal transition or postmenopausal phase, and are also intended to raise awareness of VVA. Recent data clearly indicate VVA is a highly prevalent condition among postmenopausal women, and that the vast majority of women with VVA are not adequately treated. In reality, diagnosis of VVA is simple and largely clinical. Many types of treatments are available for VVA, ranging from preventive education measures to local non-hormonal therapies, local agents that modulate hormonal receptors and systemic as well as laser therapy and radiofrequency. Regardless of the therapeutic approach adopted, greater communication between the physician and the woman with VVA should be actively encouraged. This is also in light of the difficulty of talking about the VVA and related disorders. Greater communication also encourages adequate therapy and thus minimizes the impact of VVA on the quality of life of the woman and her partner.

Real-world Adherence and Persistence with Bisphosphonate Therapy in Postmenopausal Women: A Systematic Review.

PURPOSE: Bisphosphonate therapy is a well-established and effective treatment for postmenopausal osteoporosis and the prevention of osteoporotic fracture. However, poor adherence to and poor persistence with bisphosphonate therapy may reduce its benefits. Previous studies have documented the poor rates of adherence and persistence among postmenopausal women with osteoporosis. The objective of this systematic literature review was to evaluate adherence, persistence, and the impact of adherence and persistence on fracture risk in postmenopausal women with diagnosed osteoporosis. METHODS: Articles eligible for review included observational studies of the real-world use of bisphosphonates in 23 countries and were identified by using MEDLINE, EMBASE, IMSEAR (Index Medicus for South-East Asia Region), and LILACS (Latin American and Caribbean Health Sciences Database). FINDINGS: We identified and evaluated 10 studies that assessed bisphosphonate adherence by measuring medication possession ratio (MPR), persistence, and/or the impact of adherence and persistence on fracture risk. Mean MPR at 1 year ranged from 54% to 71% in the 3 studies that reported this assessment of adherence, and 40%-85% of patients at 1 year were adherent, defined as an MPR ≥80%, in the 8 studies that reported this end point. At 1 year, rates of persistence ranged from 28% to 74%. Rates of adherence and persistence were highest with agents requiring less frequent administration and typically declined over time. Fracture rates were significantly lower among adherent women with MPRs ≥80% compared with women with MPRs <80%. IMPLICATIONS: Our results show that suboptimal adherence to and persistence with bisphosphonate therapy in postmenopausal women are common and increase the risk of fracture. Additional research is needed to identify and incorporate effective strategies for improving adherence to bisphosphonates in postmenopausal women.