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.

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.

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.

Non-hormonal strategies for managing menopausal symptoms in cancer survivors: an update.

Vasomotor symptoms, particularly hot flushes (HFs), are the most frequently reported symptom by menopausal women. In particular, for young women diagnosed with breast cancer, who experience premature ovarian failure due to cancer treatments, severe HFs are an unsolved problem that strongly impacts on quality of life. The optimal management of HFs requires a personalised approach to identify the treatment with the best benefit/risk profile for each woman. Hormonal replacement therapy (HRT) is effective in managing HFs but it is contraindicated in women with previous hormone-dependent cancer. Moreover, many healthy women are reluctant to take HRT and prefer to manage symptoms with non-hormonal strategies. In this narrative review, we provide an update on the current available non-oestrogenic strategies for HFs management for women who cannot, or do not wish to, take oestrogens. Since isoflavones have oestrogenic properties and it is not known if they can be safely consumed by women with previous hormone-dependent cancer, they were excluded. Selective serotonin reuptake inhibitors/selective serotonin-norepinephrine reuptake inhibitors, as well as other neuroactive agents, some herbal remedies and behavioural strategies are considered.

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.

Estrogen-related seizure exacerbation following hormone therapy for assisted reproduction in women with epilepsy.

PURPOSE: Exogenous estrogens might lead to seizure worsening in women with epilepsy (WWE) by lowering the seizure threshold and inducing glucuronidation in women taking lamotrigine. Assisted reproduction techniques are increasingly used and often require estrogenic and estrogen raising hormone therapy. We aimed at reporting their possible impact on seizures in WWE. METHODS: We describe two cases of seizure exacerbation following hormone therapy for assisted reproduction in WWE. RESULTS: Patient 1: 46 years old woman, with right temporal dysplasia. At 40 years she had monthly focal seizures, possibly progressing to bilateral tonic-clonic seizures, she took levetiracetam 3000/day and she underwent gonadotropin therapy for ovarian stimulation. Estrogen blood levels showed a sudden and significant rise, up to 1019 pg/ml and she had a concomitant cluster of three tonic-clonic seizures in 24 h. Patient 2: 41 years old woman with focal epilepsy of unknown etiology. At 38 years she was taking lamotrigine 450 mg/day and had been seizure free for three years. She took estradiol valerate 4 mg for 10 days for endometrial preparation for embryo transfer and had the only seizure over six years, with the exception of auras during advanced pregnancy, related to marked decrease of lamotrigine blood levels. During adjunctive concomitant therapy with clobazam, neither patient had seizures while on hormone therapy. CONCLUSIONS: Our data suggest that hormone therapy for assisted reproduction could exacerbate seizures and should be carefully monitored in WWE, especially those taking drugs inactivated by glucuronidation. Adjunctive concomitant antiepileptic therapy should be considered.

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.

Effect of Estradiol valerate plus dienogest on body composition of healthy women in the menopausal transition: a prospective one-year evaluation.

In the menopausal transition (MT), combined oral contraceptive (COC) should be chosen accordingly to its neutrality on liver metabolism and to its ability to counter the increase of fat mass (FM) that occurs in this reproductive period of life. This prospective multi-centric observational study was conducted on 36 women in their MT at the Universities of Cagliari, Modena and Naples. The body weight (BW), the Body Mass Index (BMI), the waist to hip ratio (WHR), the measurement of body composition (BC) with the Multi-frequency Bioelectrical Impedance (MF-BIA) were performed before, at the 6th and at the 12th month of the study in which a group of women (control group; N.18) did not assume COC, whereas the other 18 women assumed the four-phasic COC containing estradiol valerate (EV) associated with dienogest (EV/DNG group). In comparison to controls in the EV/DNG group, a significant decrease (p < 0.05) of BW (58.8 ± 7.6 to 57.3 ± 7.0), BMI (24.1 ± 2.7 to 23.5 ± 2.8), WHR (0.82 ± 0.052 to 0.79 ± 0.048) and FM (17.7 ± 5.4 to 16.4 ± 5.6) was observed. In controls, FM significantly increased (17.0 ± 11 to 17.7 ± 2.7; p < 0.05). In conclusion, these results suggest that the anti-androgenic and progestinic activities of DNG associated with a weak estrogenic activity of EV, is a contraceptive method capable of counteracting the negative changes of BC occurring in the MT.

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.

Haemostatic and metabolic impact of estradiol pills and drospirenone-containing ethinylestradiol pills vs. levonorgestrel-containing ethinylestradiol pills: A literature review.

OBJECTIVE: Since its introduction 50 years ago, the contraceptive pill has continuously evolved to decrease the risk of venous thromboembolism (VTE) associated with its use. An increased risk of VTE still remains, however. Other concerns, such as effects on lipid and carbohydrate metabolism, have also been reported. In this study we compared two reference combined oral contraceptives (COCs) containing ethinylestradiol (EE)/levonorgestrel (LNG) and EE/drospirenone (DRSP) with COCs containing estradiol (E2) (estradiol valerate [E2V]/dienogest [DNG] and E2/nomegestrol acetate [NOMAC]). They were evaluated according to their influence on recognised haemostatic and metabolic markers. METHODS: A literature search of the MEDLINE/PubMed database was conducted for head-to-head studies. EE/LNG was chosen as the comparator pill. RESULTS: The haemostatic impact of E2 pills and EE/LNG has been extensively compared, in contrast to that of EE/DRSP and EE/LNG. Changes in haemostatic and metabolic marker levels between EE/LNG and E2V/DNG were generally not statistically significant. E2/NOMAC showed statistically significantly favourable results on haemostatic markers and had a neutral effect on carbohydrate and lipid metabolism when compared with EE/LNG. CONCLUSION: E2/NOMAC exhibits less haemostatic and metabolic impact than EE/LNG and other COCs, suggesting that it may be a promising candidate to reduce residual VTE risk associated with COC use. Confirmation from a well-powered prospective clinical trial is, however, needed.

Effects of estroprogestins containing natural estrogen on vaginal flora.

Estroprogestins with "natural oestrogen" has represented a new option in terms of combined hormonal contraception. So, the aim of this study is to investigate how estroprogestins with natural estrogen may modify the vaginal niche. In literature, very few studies focused on the interaction between hormonal contraception and vaginal milieu. This is a prospective comparative study. We enrolled 60 women from January 2013 to September 2013, 30 of them were administered estradiol valerate dienogest (E2V+DNG - Klaira®) in a quadriphasic regimen, while the other 30 women were administered 17-ß estradiol with nomestrol acetate (EV+NOMAC - Zoely®) in a monophasic regimen. After a baseline study of vaginal milieu at recruitment of patients (Gram stain with Nugent score, vaginal pH, vaginal wet mount for the quantification of leukocytes, Lactobacilli and/or presence of Candida), we performed the same follow-up after six months of estroprogestin therapy. Our results showed that the women treated with E2V+DNG had a trend of an improvement of vaginal health in terms of increase of lactobacillar flora and reduction of vaginal pH in place of women treated with EV+NOMAC that showed a reduction of cervical mucus. Finally, our data about the effects on vaginal flora exerted by two estroprogestin pills (EPs) containing a natural estrogen suggest slight, but interesting differences in terms of vaginal ecology. These differences could be related to the type of estrogen, type of progestin, regimen of administration and, after all, to the net balance between estrogenic and progestin component of the EPs.

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.

Profile of bazedoxifene/conjugated estrogens for the treatment of estrogen deficiency symptoms and osteoporosis in women at risk of fracture.

Decreasing levels of estrogens during menopause are associated with reduced bone density and an increased risk of osteoporosis. Many women also experience bothersome vasomotor and vaginal symptoms during the menopausal transition. Results of systematic reviews and meta-analyses of randomized controlled trials have shown that both systemic estrogen therapy or hormone therapy (estrogen combined with a progestin) are useful to prevent bone loss, and they are the most effective treatment for such climacteric symptoms as hot flushes, sweating, vaginal dryness, and dyspareunia. Unfortunately, estrogen therapy and hormone therapy increase the risk of endometrial and breast cancer, respectively. The selective estrogen receptor modulators (SERMs) result in positive estrogenic effects on bone, with no negative effects on the endometrium and breast but do not provide relief from postmenopausal symptoms. The combination of a SERM with estrogen as a tissue selective estrogen complex (TSEC) is a new strategy for the prevention of bone loss and the treatment of climacteric symptoms. This combination is particularly interesting from a clinical point of view, taking into account that estrogen alone did not increase breast cancer risk by the Women's Health Initiative. TSEC is hypothesized to provide the benefits of estrogen-alone therapy, with an improved tolerability profile because the SERM component can make possible the elimination of progestin. The objective of this review was to critically evaluate the evidence from the reports published to date on the use of bazedoxifene (a third-generation SERM) in combination with conjugated estrogens in postmenopausal women. The conclusion is that effectively, the combination of bazedoxifene and conjugated estrogens may be a promising alternative to hormone therapy for the prevention of osteoporosis and the treatment of postmenopausal symptoms in non-hysterectomized postmenopausal women.