Background: The menopausal transition may be accompanied by several disabling symptoms which impair quality of life. Many women cannot proceed with and/or refuse hormonal replacement therapy (HRT) and, thus, they rely on non-hormonal remedies to manage climacteric syndrome. Methods: This was a retrospective study analyzing the impact of a combination of Purified Cytoplasm of Pollen (PCP) with vitamin D (vitD) and vitamin K2 (vitK2) on menopausal symptoms and bone parameters in a sample of symptomatic women (Group A, n = 22) compared to controls (Group B, n = 23). Results: We found that blood levels of vitD (25OHD) significantly increased within Group A (p = 0.0004) whereas no significance was reached within Group B (p > 0.05) after a three-month therapy. Compared with the baseline, serum C-terminal telopeptide of type I collagen (CTX) turned out to be significantly reduced within Group A (p = 0.0415) but not within Group B (p > 0.05). Comparing Group A and Group B, the values of CTX significantly differed after treatment (p = 0.0458). In comparison to the baseline, significant differences emerged within Group A for physical, psychosocial, and vasomotor domains of Menopause-Specific Quality of Life (MenQol) (p < 0.05) whereas no significant difference was found for the sexual domain (p > 0.05). Comparing Group A and Group B, significant differences were observed for all MenQol domains (p < 0.05), except for the sexual domain (p > 0.05) after therapy. Conclusions: Based on our findings, the combination of PCP, vitD, and vitK2 could be used for managing vasomotor and mood disturbances associated with menopause, whilst also offering the added benefit of maintaining bone health.

INTRODUCTION:The influence of thyroid autoimmunity (TAI) on obstetrical and fetal outcomes is debated. Specifically, the impact of thyroid antibodies on the risk of recurrent pregnancy loss (RPL) remains controversial. Similarly, the relationship between glucose metabolism and vitamin D (vitD) status in RPL women needs clarification. METHODS:We evaluated 301 non-pregnant women (mean age 37 ± 4.8 SD) with a previous history of primary RPL (≥ 2 spontaneous pregnancy losses < 20 weeks of gestation) referred to our clinic over a period of 5 years (from 2020 to 2025). RESULTS:We did not find significant correlations between TAI and full-term pregnancies or abortions (p > 0.05). ANOVA analysis showed that the variables "full-term pregnancies" and "abortions" significantly impacted TSH (p = 0.007 and p = 0.011, respectively), whereas no significant results emerged for the dependent variables free thyroxine (fT4) and free triiodothyronine (fT3) (p > 0.05). No statistically significant correlations were found between TAI and the area under the glucose curve (AUC-Glyc) or between TAI and the area under the insulin curve (AUC-Ins) (p > 0.05). We did not find significant associations between TAI and previous gestational diabetes mellitus (GDM) (p > 0.05) or between vitD and TAI (p > 0.05). DISCUSSION:TAI did not appear to influence RPL risk in non-pregnant euthyroid women. A broader clinical evaluation may be more appropriate to determine the actual risk of miscarriage. CONCLUSIONS:TAI alone did not seem to strongly impact the rate of miscarriages, glucose metabolism, or vitamin D status in non-pregnant women with RPL.

INTRODUCTION:Combined oral contraceptives (COCs) have undergone continuous pharmacological evolution since their introduction in the 1960s. The replacement of synthetic ethinyl estradiol (EE) with natural estrogens - estradiol (E2), estradiol valerate (E2V), and estetrol (E4) - represents a significant advancement in improving the tolerability, safety, and acceptability of hormonal contraception. AREAS COVERED:This paper surveys the extensive literature existing on the historical and pharmacological evolution of COCs, with particular focus on the role of the estrogenic component in balancing efficacy and tolerability. The pharmacokinetic and pharmacodynamic profiles of available estrogens are discussed, highlighting the distinctive properties of estradiol, estradiol valerate and estetrol. Evidence from clinical trials and observational studies supporting a favorable metabolic, hemostatic, and cardiovascular profile of natural estrogen-based COCs is reviewed, alongside emerging data supporting their designation as a first-line contraceptive option. EXPERT OPINION:Natural estrogens represent the culmination of approximately 70 years of COC development. Their incorporation into clinical guidelines as first-line options requires comprehensive awareness among healthcare providers and broader access for users. Further lines of research may focus on pharmacological optimization and long-term safety across diverse populations as in women with comorbidities to fully realizing their clinical wide potential.

The publication of the study WHI (Women's Health Initiative) represented a critical moment for the management of menopause considering the alarming results about breast cancer and cardiovascular risks. Anyway, several further studies progressively clarified over time the effective clinical impact of hormone replacement therapy (HRT) among post-menopausal women if adequately started before the age of sixty and no more than ten years after the last menstrual cycle and properly customized according to the major international recommendations. Robust evidence exists on different approved bioidentical HRT (abHRT) but data about galenic composed bioidentical hormone therapy (cbHRT) remain poor. The purpose of this expert opinion is to elucidate the position on Hormone Therapy with Bioidentical Hormones of the major Italian societies dealing with menopause, that is the Italian Society of Gynecology of the Third Age (SIGiTE) and the Italian Society of Menopause (SIM), in order to aware physicians about the suitability of their use.

INTRODUCTION:Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine-metabolic syndrome mainly characterized by ovarian dysfunction, which is only one manifestation of a more complex syndrome with a significant systemic impact. EVIDENCE ACQUISITION:We review scientific literature on the pathophysiology and diagnosis of PCOS evaluating the most relevant data from original articles, reviews and meta-analyses published until June 2024. EVIDENCE SYNTHESIS:From a pathophysiological point of view, the concurrence of both metabolic aspects, such as insulin resistance and obesity, and hormonal alterations, such as hyperandrogenemia, might produce the most relevant clinical signs and/symptoms of this syndrome, for instance menstrual irregularities, hair loss, acne and hirsutism. In the latest years, many pieces of evidence highlighted the importance of family history and genetics in the development of the syndrome during adolescence and adult life. According to the available data, hypovitaminosis D could play a detrimental role in the pathogenesis and clinical manifestations of PCOS. CONCLUSIONS:PCOS is a challenging endocrine and metabolic dysfunction, due to its different expression among women and to the difficulty in obtaining an accurate diagnosis. The most appropriate approach to women affected by PCOS should involve a multi-step strategy, taking into account the characteristics of each patient, in order to identify the best non-pharmacologic and pharmacologic approach to manage both short- and medium-, and long-term sequelae.

INTRODUCTION:Clinical characteristics of polycystic ovary syndrome (PCOS) (menstrual irregularities, obesity, anovulation, etc.), occur together with a series of conditions at skin level like seborrhea, acne, hirsutism, and androgenetic alopecia. Estroprogestins (EPs) are recognized as the most powerful therapy to treat hyperandrogenism and/or hyperandrogenemia and regularize menstrual cycle. EVIDENCE ACQUISITION:This review includes the most relevant publications about the effects of EPs in PCOS women published between 1995 and 2025. EVIDENCE SYNTHESIS:According to the available data, EPs composed by an anti-androgenic progestin appear the most suitable to reduce the hyperandrogenic manifestations of PCOS. More specifically, cyproterone acetate (CPA), drospirenone (DRSP) and dienogest (DNG) associated with 20-30 μg of ethinylestradiol (EE) seem to be the most effective compounds for the management of androgen excess. As the benefit risk/ratio of the association EE/CPA is less favorable, the use of EPs with other antiandrogenic progestins could be more appropriate to treat PCOS patients, also from a metabolic point of view. CONCLUSIONS:In conclusion, an aware choice of the most adequate and tolerable EP formulation according to the pharmacological profile and individual characteristics of PCOS patient is essential to opportunely customize the treatment of androgen excess.

BACKGROUND:Polycystic ovary syndrome (PCOS) is an endocrine/metabolic condition. Hyperandrogenism and insulin-resistance with compensatory hyperinsulinemia are important features of PCOS. The aim of this paper is to review the rationale of antiandrogens and insulin-sensitizers use in PCOS management. EVIDENCE ACQUISITION:We include in our research the most relevant scientific literature about the impact of antiandrogens and insulin sensitizers in PCOS between 1976 and 2025. EVIDENCE SYNTHESIS:According to the most recent recommendations, antiandrogens can be a possible therapeutic option to reduce the impact of hyperandrogenism and treat hirsutism in PCOS patients after a period of 6 months of estroprogestins and/or cosmetic therapy without adequate results. Insulin-sensitizers can decrease the levels of insulin in subjects affected by hyperinsulinemia, improving metabolic and hormonal alterations observed in PCOS patients. CONCLUSIONS:Antiandrogens and insulin sensitizers represent fundamental pharmacological therapies for PCOS management.

INTRODUCTION:Polycystic ovary syndrome (PCOS) is a multifactorial endocrine-metabolic disease that requires pharmacological and non-pharmacological treatments. The aim of this paper is to review the major evidence about current lifestyle and dietary approaches to manage this syndrome. EVIDENCE ACQUISITION:We include in our research the most relevant publications about lifestyle and diet in PCOS published between 1995 and 2025. EVIDENCE SYNTHESIS:According to the most recent recommendations, regular physical activity is crucial to ameliorate hormonal and metabolic parameters as well as to maintain and/or reduce weight in PCOS women. As for the foods, although there is not agreement on a specific diet, low-glycemic index nutrients associated with high fiber intake should be generally preferred in hyperinsulinemic patients. CONCLUSIONS:In conclusion, suggestions about lifestyle and diet should represent a cornerstone of the personalized multi-step therapy of PCOS.

BACKGROUND:Osteoporosis is a chronic disease affecting individual, public and social health. Few data are available about the awareness of osteoporosis in Italy. The main purpose of our study is to evaluate the perception of osteoporosis in a selected sample of subjects of different age and sex. METHODS:This is a survey involving 299 adults (aged 18-75 years) designed to assess knowledge about osteoporosis and fracture risk conducted by a multidisciplinary research team of LUISS Guido Carli University. RESULTS:The knowledge of osteoporosis resulted almost high among the participants (97%) and most of them considered it a disease (86.1%). Most respondents (30.5%) did not know if they might be at risk of osteoporosis, especially the youngest (43.5%). A high percentage of participants (73.8%) considered a family history of osteoporosis the principal risk factor for bone loss, while only 8.9% thought that moderate to vigorous physical activity could favor bone loss. Many women (17.4%) did not consider menstrual irregularities a risk factor for osteoporosis. As for nutrients, 79.5% and 89.4% of subjects, respectively, thought that vitamin D and calcium might be useful to prevent bone loss. The majority of sample (74.8%) did not know the public and social impact of osteoporosis. CONCLUSIONS:Although this survey involved a selected population and, thus, it cannot reflect the Italian general knowledge of osteoporosis, it might contribute to estimate the actual awareness of osteoporosis among people, regardless of their current bone health status, highlighting areas for further educational and research efforts.

Premature ovarian insufficiency (POI) is a critical condition affecting young women before the median age of menopause and consisting of spontaneous oligo-amenorrhea for at least four months associated with follicle stimulating hormone (FSH) levels ≥25 UI/L detected before 40 years of age. Several causes like genetic abnormalities, autoimmune diseases, drugs and/or pelvic surgery may favor this condition that is associated with a deeper clinical impact on women's health compared to physiological menopause. Specifically, cardiovascular and musculoskeletal systems as well as brain could be especially affected by the early loss of ovarian hormones. Therefore, appropriate treatment is necessary to adequately narrow the biological gap with the average age of menopause. Hormone replacement therapy (HRT) is the treatment of choice, regardless of the presence of neurovegetative symptoms. Transdermal high dosage of natural estradiol is generally preferred to guarantee the preservation of cardio-metabolic and bone health. When contraception is required, oral estroprogestins (EPs) maybe considered. A referral to reproductive experts for fertility preservation techniques should be considered case by case.

BACKGROUND: The primary purpose of this study was to verify if trabecular bone score (TBS) might fit with the changes of bone mineral density (BMD) confirming as a reliable marker of bone fragility. METHODS: A retrospective observational study on 898 Italian women (aged 40-90 years) was conducted between January 2021 and February 2023. All recruited women were divided into two main groups according to TBS (Group A: TBS >= 1.31; Group B: TBS<1.31) and, further, in five subgroups according to age. RESULTS: According to univariate ANOVA, there was not significant difference of BMI between group A and group B but Bonferroni Test found that BMI significantly differed for age subgroups and TBS value (P<0.05). ANOVA analysis reported that mean L1-L4 BMD and/or T-score were significantly different for age and TBS (P=0.000); Bonferroni Test found that L1-L4 BMD significantly differed in the comparison of age subgroups for Group A and Group B (P<0.05). Besides, Bonferroni analysis found significant differences regarding total and neck femoral BMD and/or T-score in the comparison between age subgroups for group A and group B (P<0.05). As for neck femoral BMD and T-score, all significances were observed for group B in the comparison between subgroups aged over 60 years and others (P<0.05). Multivariate logistic regression analysis showed that age and femoral neck BMD significantly contribute to TBS (P<0.05). CONCLUSIONS: Our results seem to suggest that low level of TBS may detect patients that could be more prone to bone frailty consistently with age and BMD at both vertebral and cortical level. However, its role in clinical practice should be refined.

Menopause maybe associated with several short, medium and long-term consequences. Metabolic disturbances represent a significant negative effect of the progressive reduction of estradiol as well as of the increased androgens/estrogens ratio occurring during perimenopause (1). Besides, other hormonal (such as, hypercortisolism and/or altered thyroid function) or non-hormonal (family hystory, dietary habits, smoking, alcohol consumption, etc.) factors, could negatively impact on metabolism in an individualized manner. On the other hand, the ageing per se usually favours a change of body composition characterized by a reduction of lean body mass (LBM) and an increase of fat free mass (FFM), exposing post-menopausal women to higher cardiometabolic risk.

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.

Osteoporosis is a systemic skeletal disease, characterized by a decrease of bone mass and bone quality, with a subsequent reduction of bone strenght and an increased risk of fracture. Hormone Therapy for menopausal women can significantly prevent osteopenia and osteoporosis, thus reducing the fracture risk. The use of HT, according to guidelines, is for postmenopausal women within 10 years since last menstruation or under the age of 60 years. Only HT at standard dose is able to reduce the fracture risk, while low-dose HT can prevent bone loss. Estrogens (with and without the addition of a progestin) and tibolone showed a fracture risk reduction effect. Also Tissue Selective Estrogen Complex (TSEC) can reduce the bone loss in postmenopause. For women without climacteric symptoms (as hot flushes and/or night sweats) the use of Selective Estrogen Receptor Modulators (SERMs) can be indicated, with a reduction of risk of vertebral fracture (for raloxifene and bazedoxifene), and non-vertebral fracture in high-risk women (for bazedoxifene). In more advence ages, antiresoptive agents as Bisphosphonates (Alendronate, Risedronate, Ibandronate and Zoledronate) can reduce the risk of vertebral, non-vertebral and hip fracture risk. Denosumab (DMAB), monoclonal antibobody against Rank-ligand (RANKL), providing an increased bone mass, significantly decreases risk of vertebral, non-vertebral and hip fracture. A drug holiday or treatment interruption is not recommended with DMAB, and DMAB dosing should not stopped without subsequent antiresorptive or other therapy to prevent a "rebound effect" with a possible increased risk of multiple vertebral fracture. Teriparatide (fraction 1-34 of recombinant PTH, administered daily 20 mcg sc) can stimulate osteoblast activity, with an important increase of bone mass and a significant reduction of risk of vertebral fracture, and of multiple vertebral fractures, but also of non-vertebral fragility fracture. Romosozumab (RMZ, adimnistered monlty 210 mg sc), is a bone-forming monoclonal antibody that binds to and inhibits sclerostin, with a dual effect of increasing bone formation and decreasing bone resorption. RMZ has showed to give marked increases in spine and hip bone density after 1 year of administration, also reducing fracture risk. The differences among the various treatments is the basis for the individualization of osteoporosis treatment, according to combination and/or sequential regimens of administration.

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.

BACKGROUND: Purified cytoplasm of pollen (PCP) is a non-hormonal herbal remedy used to manage vasomotor symp-toms (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 treat-ment for the management of VMS as well as mood and sleep disturbances in both peri-and post-menopause. (Cite this article as: Lello S, Capozzi A, Xholli A, Cagnacci A; Italian Society of Menopause (SIM); Italian Society of Gy-necology of the Third Age of Women (SIGiTE); the Pollen Extract in Menopause Italian Study Group. The benefits of puri-fied cytoplasm of pollen in reducing menopausal symptoms in peri-and post-menopause: an Italian multicenter prospective observational study. Minerva Obstet Gynecol 2022;74:516-21. DOI: 10.23736/S2724-606X.21.04964-2)

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.

SommarioL’osteoporosi postmenopausale è un processo per il quale il tessuto osseo sviluppa una fragilità risultando più suscettibile alle fratture anche per traumi che solitamente non comporterebbero tali eventi. La carenza estrogenica è un punto fondamentale nella patogenesi dell’osteoporosi. La TOS rappresenta un trattamento di scelta nella prevenzione della osteoporosi e delle fratture correlate, soprattutto nei primi anni di postmenopausa.

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.

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.