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.

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.

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.

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.

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.

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.

Treatment with d-chiro-inositol and alpha lipoic acid in the management of polycystic ovary syndrome.

To evaluate the effects of the combination of d-chiro inositol and alpha lipoic acid on menstrual cycles and insulin sensitivity in women with polycystic ovary syndrome (PCOS). Forty-one women with PCOS and 31 controls have been enrolled in the study. The menstrual cycle, BMI, homeostasis model assessment index (HOMA-I), and insulin secretion in response to an OGTT were evaluated before and after 6 months of treatment. During the observation period, the patients have been asked to not modify their diet and physical activity. The menstrual cycle length improved in 76.7% of the women. Ovulation was restored in 40%. During treatment, BMI significantly decreased (p<.002). The HOMA-I and insulin secretion were unchanged by treatment. However, when women were divided according to the presence of insulin resistance (IR; HOMA-I > 2.5), in those with IR the HOMA-I and the insulin secretion significantly decreased (p<.05 and p<.006). The association of d-chiro-inositol and alpha lipoic acid improves menstrual cycle length, restoring ovulation in the majority of women. Insulin sensitivity improved in women with IR only, confirming that in presence of IR the d-chiro-inositol has a role in restoring the insulin action overcoming the inactivity of epimerase in transforming myo-inositol to d-chiro inositol.

A Rare Case of Systemic AL Amyloidosis with Muscle Involvement: A Misleading Diagnosis.

Muscle involvement in AL amyloidosis is a rare condition, and the diagnosis of amyloid myopathy is often delayed and underdiagnosed. Amyloid myopathy may be the initial manifestation and may precede the diagnosis of systemic AL amyloidosis. Here, we report the case of a 73-year-old man who was referred to our center for a monoclonal gammopathy of undetermined significance (MGUS) diagnosed since 1999. He reported a progressive weakness of proximal muscles of the legs with onset six months previously. Muscle biopsy showed mild histopathology featuring alterations of nonspecific type with a mixed myopathic and neurogenic involvement, and the diagnostic turning point was the demonstration of characteristic green birefringence under cross-polarized light following Congo red staining of perimysial vessels. Transmission electron microscopy (TEM) confirmed amyloid fibrils around perimysial vessels associated with collagen fibrils. A stepwise approach to diagnosis and staging of this disorder is critical and involves confirmation of amyloid deposition, identification of the fibril type, assessment of underlying amyloidogenic disorder, and evaluation of the extent and severity of amyloidotic organ involvement.

Clinical management of osteoporotic vertebral fracture treated with percutaneous vertebroplasty.

Our study demonstrated percutaneous vertebroplasty (PVP) is an effective procedure to rapidly reduce back pain in patients affected by acute osteoporotic vertebral compression fractures (OVCFs) assessed by MRI. We confirmed in our sample, femoral bone density impacts more deeply than vertebral T-score and/or BMD on bone strenght, as it is less affected by any interferences. We interestingly found the presence of previous osteoporotic fragility fractures and chronic glucocorticoids therapy should especially negatively influence bone health of our patients. On the other hand, even if both FRAX scores for major osteoporotic fractures and for femoral fractures seemed to globally define a population at major risk for fragility fractures, our analysis is retrospectively done. We choose and suggest a multidisciplinary medical management of these patients, considering OP is a multifactorial disease and OVCFs usually produce lots of different important consequences on general health.

The Tissue-Selective Estrogen Complex (Bazedoxifene/Conjugated Estrogens) for the Treatment of Menopause.

The tissue-selective estrogen complex (TSEC) pairs conjugated estrogens (CE) with a selective estrogen receptor modulator (SERM), bazedoxifene acetate (BZA). A 2-year treatment with the TSEC improved vasomotor symptoms, quality of life, and vaginal atrophy in healthy postmenopausal women. In addition, the TSEC prevented vertebral and hip bone loss without increasing mammographic density, breast tenderness, the risk of myocardial infarction, stroke, or venous thromboembolism. Finally, the BZA 20 mg/CE 0.45 mg dose did not increase the risk of endometrial hyperplasia. Based on these findings, the TSEC can be considered as a first-line treatment for symptomatic postmenopausal women.

Hyperprolactinemia: pathophysiology and therapeutic approach.

Prolactin (PRL) is a hormone, mainly secreted by lactotroph cells of the anterior pituitary gland. Recent studies have shown it may also be produced by many extrapituitary cells. Its well-recognized PRL plays an important role in lactation during pregnancy, but it is involved in other biological functions such as angiogenesis, immunoregulation and osmoregulation. Hyperprolactinemia is a typical condition producing reproductive dysfunction in both sexes, resulting in hypogonadism, infertility and galactorrhea. It may be also asymptomatic. Lactotroph adenomas (prolactinoma) is one of the most common cause of PRL excess, representing approximately 40% of all pituitary tumors. Several other conditions should be excluded before a clear diagnosis of hyperprolactinemia is made. Hyperprolactinemia may be secondary to pharmacological or pathological interruption of hypothalamic-pituitary dopaminergic pathways or idiopathic. Stress, renal failure or hypothyroidism are other frequent conditions to exclude in patients with hyperprolactinemia. We will review biochemical characteristics and physiological functions of that hormone. Clinical and pharmacological approach to hyperprolactinemia will also be discussed.

The inhibition of RANK-ligand in the management of postmenopausal osteoporosis and related fractures: the role of denosumab.

There is great interest in new treatments of osteoporosis owing to general ageing of population and increased risk for fragility fractures in the elderly. Current therapies show a good efficacy in improving bone quality and bone density, but, in spite of a certain reduction in fracture rate, according to each treatment, the problem of osteoporotic fractures is yet far from to be solved. Moreover, some treatments may produce different side effects. Denosumab (Dmab), a receptor activator of nuclear factor kappa-B ligand (RANKL)-inhibitor, is an agent recently introduced in clinical practice for treatment of osteoporosis of postmenopausal women. Dmab has improved bone mineral density and prevented new vertebral and non-vertebral fractures with a similar efficacy in comparison with alendronate. Many clinical studies showed Dmab produces also significant improvement versus placebo in bone quality as indicated by decreasing markers of bone turnover. Patients using Dmab reported less risk of AFF (Atypical Femoral Fractures) and ONJ (Osteonecrosis of the Jaw) with an increased number of cellulitis. Here, we review articles using Dmab for female post-menopausal osteoporosis.

Vertebra plana: reappraisal of a contraindication to percutaneous vertebroplasty.

PURPOSE: We evaluated the efficacy of percutaneous vertebroplasty (PVP) in treating symptomatic vertebra plana, which is considered a relative contraindication to the procedure. METHODS: Out of 540 levels treated in 260 patients, we treated 40 patients (mean age: 74 years) with vertebra plana between T6 and L3 (37 osteoporotic and 3 metastatic levels). In most cases, the vertebra was accessed with fluoroscopic guidance from a single, transpedicular approach. All patients underwent a preliminary MRI examination, an immediate, post-procedure radiological examination, and a follow-up examination (mean duration, 6 months). RESULTS: Both immediate and follow-up examinations showed that the mean pain and physical disability scores were significantly reduced compared to the scores before treatment (p ≤ 0.001). No complications occurred during the procedures. In 23/40 cases, asymptomatic intradiscal cement leakage occurred. Posterior or perivertebral leakage never occurred. In most cases, an intravertebral cleft was present, and we filled it with polymethylmethacrylate, which healed the pseudarthrosis. Partial vertebral height was restored in 7 cases. In 6 cases, a new fracture occurred between 1 and 3 months at a different level from the treated level. CONCLUSION: Our preliminary results showed that PVP was a safe, effective treatment for symptomatic vertebra plana; thus, it should not be discounted for this group of patients. In most cases, the procedure was favored by the presence of an intravertebral cleft that appeared to contribute to minimizing the risk of posterior cement leakage. Filling the cleft with polymethylmethacrylate allowed intravertebral stabilization.

Chronic low-dose glucocorticoid inhalatory therapy as a cause of bone loss in a young man: case report.

Osteoporosis in men is less frequent than in women and is more often due to an underlying cause, such as nutritional deficiencies or lifestyle factors, endocrinological or systemic affections, long-term specific therapies. The growing attention on male osteoporosis is mainly explained by the increasing use of some drugs producing bone loss as frequent side effect, like gonadotropin-releasing hormone (GnRH) agonists for prostate cancer, immunosuppressive agents, or glucocorticoids. Glucocorticoids are largely used for the cure of lots of haematological, rheumatological, dermatological, pneumological, and other systemic diseases. It is well known glucocorticoid-induced osteoporosis (GIOP) develops rapidly at prednisone > 5mg/d or equivalent levels but recurrence is recently also observed in patients receiving low dose and intermittent therapy. However, the possible side effects of corticosteroids at low dose on bone are not completely understood and rightly prevented. We present the case of a young man with precocious bone loss. His improper and irregular use of corticosteroids at low dose was finally recognized as the underlying cause of his unexplainable bone demineralization. The following short review about effects of glucocorticoids on bone suggests fracture incidence and bone mineral density should be assessed even in young people and men perceiving glucocorticoids at undefined dose for long period.