Publications by authors named "Stefano Luisi"

120 Publications

Management of perimenopause disorders: hormonal treatment.

Gynecol Endocrinol 2021 Mar 2;37(3):195-200. Epub 2020 Dec 2.

Department of Molecular and Developmental Medicine, Obstetrics and Gynecology, University of Siena, Siena, Italy.

Perimenopause represents a transition period of a woman's life during which physiological, affective, psychological, and social changes mark progression from a woman's fertile life to menopause, with wide sexual hormones fluctuations until the onset of hypergonadotropic hypogonadic amenorrhea. Contraception during menopause should not only avoid unwanted pregnancies, but also improve quality of life and prevent wide range of condition affecting this population. Hormonal contraceptives confer many noncontraceptive benefits for women approaching menopause: treatment of abnormal uterine bleeding, relief from vasomotor symptoms, endometrial protection in women using estrogen therapy, musculoskeletal protection, and mood disorders protection. The main point remains selecting the most adequate contraceptive option for each woman, considering her risk factor, comorbidities, and keeping in mind the possibility of continuing contraception until reaching menopause and even further, creating a bridge between perimenopause and menopause hormonal therapy. Correct perimenopause management should rely on individualized medical therapy and multidisciplinary approach considering lifestyle and food habits as part of general good health of a woman.
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http://dx.doi.org/10.1080/09513590.2020.1852544DOI Listing
March 2021

Genitopelvic pain: retrospective evaluation of a multimodal treatment efficacy.

Minerva Ginecol 2020 Jun;72(3):123-131

Department of Medical Biotechnologies, University of Siena, Siena, Italy.

Background: Genitopelvic and sexual pain penetration disorder (GPPD) recognizes a multifaceted etiology. As with syndromes of chronic pain, it responds poorly to medications and its management is difficult. Clinicians consequently favor a multimodal comprehensive approach to tackle the different aspects of the disorder. To treat GPPD women, we chose a multimodal regimen including topical and systemic medications associated with physical interventions and behavioral couple therapy. Our aim was to evaluate the regimen efficacy and the influence that demographic, clinical, and pain characteristics may have on the outcome.

Methods: Sixty self -referred women requesting medical care for GPPD, who were free of debilitating illness, in stable heterosexual relationships and with healthy and sexually functional partners, were treated according with the multimodal regimen we tailored on the specific needs of these women. As said, it associated topical and systemic medications combined with physical exercises used in behavioral sex therapy, and behavioral couple therapy. Past sexual history, characteristics of pain, vestibular hyperreactivity, pelvic floor hypertonicity, general health, and couple harmony were evaluated and statistically analyzed to determine which characteristics were associated with therapy outcome.

Results: The statistical analysis of an association between demographic, reproductive, pain and medical conditions on one hand and therapy outcome on the other did not find any significance.

Conclusions: The lack of association between the investigated characteristics and treatment outcome is disappointing; on the other hand, the statistically significant impact of couple harmony (evaluated as partner presence and participation) on the treatment results may be the answer to our search for factors predicting outcome.
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http://dx.doi.org/10.23736/S0026-4784.20.04555-4DOI Listing
June 2020

Expression of Matrix Metalloproteinases and Their Inhibitors in Endometrium: High Levels in Endometriotic Lesions.

Int J Mol Sci 2020 Apr 18;21(8). Epub 2020 Apr 18.

Department of Molecular and Developmental Medicine, Siena University, 53100 Siena, Italy.

Endometriosis is a condition defined as presence of endometrium outside of the uterine cavity. These endometrial cells are able to attach and invade the peritoneum or ovary, thus forming respectively the deep infiltrating endometriosis (DIE) and the ovarian endometrioma (OMA), the ectopic lesions feature of this pathology. Endometriotic cells display high invasiveness and share some features of malignancy with cancer cells. Indeed, the tissue remodeling underlining lesion formation is achieved by matrix metalloproteinases (MMPs) and their inhibitors. Therefore, these molecules are believed to play a key role in development and pathogenesis of endometriosis. This study investigated the molecular profile of metalloproteinases and their inhibitors in healthy ( = 15) and eutopic endometrium ( = 19) in OMA ( = 10) and DIE ( = 9); moreover, we firstly validated the most reliable housekeeping genes allowing accurate gene expression analysis in these tissues. Gene expression, Western blot, and immunofluorescence analysis of MMP2, MMP3, and MMP10 and their tissue inhibitors TIMP1 and TIMP2 demonstrated that these enzymes are finely tuned in these tissues. In OMA lesions, all the investigated MMPs and their inhibitors were significantly increased, while DIE expressed high levels of MMP3. Finally, in vitro TNFα treatment induced a significant upregulation of , , and in both healthy and eutopic endometrial stromal cells. This study, shedding light on MMP and TIMP expression in endometriosis, confirms that these molecules are altered both in eutopic endometrium and endometriotic lesions. Although further studies are needed, these data may help in understanding the molecular mechanisms involved in the extracellular matrix remodeling, a crucial process for the endometrial physiology.
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http://dx.doi.org/10.3390/ijms21082840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215833PMC
April 2020

Is Stress a Cause or a Consequence of Endometriosis?

Reprod Sci 2020 01 6;27(1):39-45. Epub 2020 Jan 6.

Department of Experimental, Clinical and Biomedical Sciences, Obstetrics and Gynecology, University of Florence, Careggi University Hospital, Largo Brambilla 3, 50134, Florence, Italy.

Clinical studies clearly indicate that endometriosis is a condition associated with high levels of chronic stress. The stress intensity correlates with pain severity and disease extension. However, it is unknown whether chronic stress represents a primary cause of endometriosis and, therefore, if avoiding or treating chronic stress may reduce the risk of developing endometriosis. Repeated, uncontrolled stress either before or after experimental endometriosis induction promotes disease mechanisms and accelerates lesion growth in rodents. Furthermore, patients with endometriosis have a heightened risk of other inflammatory and immune-related diseases, many of which have also been associated with stress. Here, we review the latest evidences regarding the relationship between chronic stress and endometriosis and discuss the potential bidirectional aspect of such association. Further research may clarify if endometriosis is a cause and/or a consequence of stress and whether stress-reducing therapies are effective to mitigate symptoms and slow down the development of endometriotic lesions.
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http://dx.doi.org/10.1007/s43032-019-00053-0DOI Listing
January 2020

Neonatal outcome in pregnancy hypotiroidee women.

Gynecol Endocrinol 2020 Sep 23;36(9):772-775. Epub 2019 Dec 23.

Department of Molecular and Developmental Medicine, Division of Obstetrics and Gynecology, University of Siena, Siena, Italy.

To evaluate the impact that hypothyroidism may have on the course of pregnancy and on neonatal outcome. This cross-sectional study consisting of 160 pregnant women (60 with hypothyroidism and 100 as control) who had been hospitalized at the Obstetrics and Gynecology of the University of Siena. The obstetric visit, the collection of anamnestic data and serum concentrations of TSH, FT4 and AbTPO were performed for each woman. Stratification of the population into two groups based on the BMI showed that there is an average difference of -0.88 before pregnancy BMI between healthy women and hypothyroid women. Moreover, with regard to the obstetric history, 8.7 times higher risk of abortion was found in hypothyroid women. About the current pregnancy in hypothyroid women, slight fetal growth delay, increased risk of premature rupture of membranes (PROM), and a higher risk of developing hypertension and gestational diabetes had been found. The importance of a more detailed anamnesis should be evaluated with greater attention at the beginning of pregnancy. This, in order to avoid the risks related to a hypothyroidism condition during pregnancy and to establish an early therapeutic treatment appropriate to the metabolic demands of each patient.
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http://dx.doi.org/10.1080/09513590.2019.1706083DOI Listing
September 2020

Autophagy up-regulation by ulipristal acetate as a novel target mechanism in the treatment of uterine leiomyoma: an in vitro study.

Fertil Steril 2019 12;112(6):1150-1159

Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy. Electronic address:

Objective: To assess the effect of ulipristal acetate (UPA) on the autophagic process of uterine leiomyoma cells.

Design: In vitro study in primary cultures of leiomyoma and myometrial cells isolated from biopsy specimen, and gene expression evaluation in biopsy material.

Setting: Cellular pathology laboratory.

Patient(s): Premenopausal women (without hormonal treatment) undergoing myomectomy or hysterectomy for symptomatic leiomyomas.

Intervention(s): Surgical specimens collected from uterine leiomyomas and matched normal myometria.

Main Outcome Measure(s): After treatment of myometrial and leiomyoma cells with UPA, autophagy was evaluated by Western blot analysis of the typical biochemical markers, LC3-II, LC3-II:LC3-I ratio, and p62/SQSTM1. The expression level of Atg7 and Atg4D proteins was also assessed by Western blot.

Result(s): The increase of LC3-II protein, LC3-II:LC3-I ratio, and p62/SQSTM1 protein indicates that UPA treatment up-regulates the autophagic response in leiomyoma cells, whereas these markers were almost unchanged in myometrial cells. Consistently, an increased level of Atg7 and Atg4D proteins was observed only in UPA-treated leiomyoma cells. The autophagic machinery is put into motion selectively in these cells, despite that the basal messenger RNA levels of LC3, SQSTM1, and ATG7 in leiomyoma biopsy specimen were not significantly different from those found in normal myometrial biopsy material.

Conclusion(s): In vitro UPA treatment stimulates the autophagic response selectively in leiomyoma cells, which adds a novel indication for the clinical use of this selective P receptor (PR) modulator. Autophagy up-regulation may potentially contribute to the leiomyoma shrinkage occurring in UPA-treated patients and warrants further study.
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http://dx.doi.org/10.1016/j.fertnstert.2019.08.007DOI Listing
December 2019

Increased expression of neurogenic factors in uterine fibroids.

Hum Reprod 2019 11;34(11):2153-2162

Dept. of Molecular and Developmental Medicine, University of Siena, Siena, Italy.

Study Question: Are selective markers for the neuronal differentiation such as microtubule-associated protein 2 (MAP-2) and synaptophysin (SYP) as well as the nerve growth factor (NGF) expressed by fibroids, myometrium and eutopic endometrium?

Summary Answer: Neuronal markers NGF, MAP-2 and SYP are highly expressed in fibroids compared with matched myometrium, and this neurogenic pathway is upregulated by tumor necrosis factor (TNF) alpha in cultured smooth muscle cells (SMCs).

What Is Known Already: Uterine fibroids or leiomyomas are the most common benign tumors, accounting for approximately one-third of hysterectomies. The present trend is to improve the medical treatment avoiding surgery, also for fertility sparing; hence, the pathogenic mechanisms are investigated, aiming to develop new therapeutic strategy.

Study Design, Size, Duration: This laboratory-based case-control study is focused on fibroids and myometrial specimens obtained between 2015 and 2017 from 15 women of reproductive age at the proliferative phase of the menstrual cycle. Leiomyomas, matched myometrium and endometrium from each woman were analyzed. Control endometrium was obtained from women undergoing surgery for ovarian cyst (n = 15).

Participants/materials, Setting, Methods: qRT-PCR, western blotting and immunostaining were applied to evaluate the expression of neurogenic markers; the effects of TNF on NGF, MAP-2 and SYP expression in cultured SMCs from leiomyomas and matched myometrium were analyzed.

Main Results And The Role Of Chance: qRT-PCR analyses using tissues from clinical patients showed that the levels of NGF, MAP-2 and SYP mRNA were significantly higher in uterine leiomyomas compared with their matched myometrium (P < 0.05), whereas only NGF was significantly increased in eutopic endometrium compared with healthy endometrium. In primary SMCs, isolated from fibroids or from the adjacent myometrium, NGF, MAP-2 and SYP mRNA expression were significantly increased by TNF treatment (P < 0.05). Finally, human endometrial stromal cells prepared from the endometrium of patients affected by uterine fibroids display higher TNF expression (P < 0.001).

Limitations, Reasons For Caution: qRT-PCR analysis and immunofluorescence validation are robust methods demonstrating a clear upregulation of neurogenic factors in leiomyomas, even though additional studies are needed to establish a correlation between increased neuronal gene expression and degree of pain, as well as the involvement of inflammation mediators in the development of the neurogenic unhinge. Therefore, more in vivo studies are needed to confirm the results achieved from primary cultured SMCs.

Wider Implications Of The Findings: The increased expression of neurogenic factors in uterine fibroids and endometrium may contribute to explain the painful stimuli. Accordingly, these neurogenic pathways may represent potential therapeutic avenues to treat the fibroid-related disorders.

Study Funding/competing Interest(s): This study was supported by research grants from the University of Siena. The authors declare no conflict of interest.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/dez182DOI Listing
November 2019

Ulipristal acetate on quality of life and sexual function of women with uterine fibromatosis.

Gynecol Endocrinol 2020 Jan 22;36(1):87-92. Epub 2019 Jul 22.

Department of Molecular and Developmental Medicine, Obsterics and Gynecology, University of Siena, Siena, Italy.

To evaluate quality of life and sexual function of childbearing-age women, affected by uterine fibromatosis undergoing medical treatment with ulipristal acetate. The data obtained by filling the questionnaires European Quality of Life Five-Dimension Scale and modified Female Sexual Function Index, were analyzed to assess UPA usefulness in improving QoL and sexual activity. A total of 139 patients affected by uterine fibromatosis undergoing conservative ulipristal acetate treatment were enrolled in this prospective observational cohort study. Seventy-one women (average age 46.5 years) answered the questionnaires: QoL and sexuality were evaluated before and after ulipristal acetate treatment. 59 patients (83.1%) had an improvement of QoL and general health state, with a reduction of VAS score after ulipristal acetate treatment. EQ-5D-5L showed a statistically significant improvement of usual act impairment, mobility, discomfort, anxiety/depression ( < .0005). There was no difference in personal care management after therapy. Modified FSFI showed a statistically significant improvement ( < .0001) of sexual satisfaction and sexual life. A not statistically significant improvement in dyspareunia was also highlighted. This study provides a clear picture about QoL impact on women and confirms the effectiveness of the ulipristal acetate in improving different aspects of daily and sexual life of patients undergoing medical treatment.
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http://dx.doi.org/10.1080/09513590.2019.1640202DOI Listing
January 2020

From β-hCG values to counseling in tubal pregnancy: what do women want?

Gynecol Endocrinol 2019 Dec 19;35(12):1021-1026. Epub 2019 Jul 19.

Division of Obstetrics and Gynecology, Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.

Tubal pregnancy represents an entity that every gynecologist will encounter during professional life. Because of the high prevalence among the pregnant population, standardized protocols are needed in order to choose the optimal strategy for each case. Accurate ultrasound pictures are supporting a more precise diagnosis of ectopic tubal pregnancy, the evolution of which should be closely monitored in follow-up with serial β-hCG values. Laparoscopy, intramuscular methotrexate, and active expectant management are all involved, however, tailoring the best treatment to the patient's needs is the challenge to focus on. This manuscript describes how in routinary practice an evidence-based diagnostic process should be the key factor to go for the best possible management. When possible, a longsighted less invasive approach should be preferred, aiming to preserve the patient's fertility for years to come. An optimal choice of the management should involve the patient or the couple in the decision-making process to reach the ultimate goal of compliance.
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http://dx.doi.org/10.1080/09513590.2019.1640201DOI Listing
December 2019

Is dienogest the best medical treatment for ovarian endometriomas? Results of a multicentric case control study.

Gynecol Endocrinol 2020 Jan 16;36(1):84-86. Epub 2019 Jul 16.

Department of Medical and Surgical Sciences, Institute of Obstetrics and Gynecology, University of Foggia, Foggia, Italy.

Ovarian endometriomas are common manifestations of endometriosis. Surgical excision has been shown to potentially decrease ovarian reserves. In this prospective study, we included 81 patients with ovarian endometriosis. 40 were treated with 2 mg of dienogest daily (DNG) and 41 were treated with cyclic oral estro-progestins (ethinyl estradiol 30 mcg [EE] plus dienogest 2 mg) (DNG + EE). Aim of the study was the effect of the treatment on the size of the endometriotic cysts. Further, in the symptomatic patients, follow-up included an evaluation of chronic pain before and during treatment. Both treatments were able to significantly decrease the pain in symptomatic patients with no statistical differences. The mean visual analog scale score at enrollment was 65 ± 14 and 70 ± 18, and there was significant improvement (19 ± 15,  < .001, DNG; 18 ± 12,  < .001, DNG + EE). The size of the endometrioma cysts were significantly reduced in the DNG group. The mean cyst diameter was 52 ± 22 mm at baseline and 32 ± 12 mm after six months of treatment ( < .001), yielding a 75% volume reduction in DNG group. The decrease in the size of endometrioma cysts observed in the women treated with only progestin could be noteworthy, as it may reduce the negative impacts on the affected ovary and avoid surgery.
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http://dx.doi.org/10.1080/09513590.2019.1640674DOI Listing
January 2020

Functional polymorphism within NUP210 encoding for nucleoporin GP210 is associated with the risk of endometriosis.

Fertil Steril 2019 08 27;112(2):343-352.e1. Epub 2019 Jun 27.

Department of Biology, University of Pisa, Pisa, Italy.

Objective: To investigate whether nucleoporin 210 (GP210, encoded by NUP210 gene) is involved in endometriosis.

Design: Immunohistofluorescence analysis for assessing whether GP210 is expressed in endometrial tissues from patients and controls; genotyping and case-control study for assessing the association between rs354476 within NUP210 and risk of endometriosis; in vitro luciferase assay for assessing the functional activity of rs354476.

Setting: University.

Patient(s): Histologically diagnosed cases (n = 175) of endometriosis: minimal or mild (stage I-II) in 48 cases (28%), moderate (stage III) in 69 cases (39%), and severe (stage IV) in 58 cases (33%). Controls (n = 557) were female blood donors collected at Meyer Hospital of Florence.

Intervention(s): None.

Main Outcome Measure(s): GP210 tissue expression; genotype distribution and risk of endometriosis; in vitro gene expression measurements.

Result(s): GP210 had positive nuclear immunohistofluorescence staining in endometrial glandular epithelium. Carriers of the variant allele were associated with increased risks: C/T, odds ratio (OR) 1.83, 95% confidence interval (CI) 1.04-3.21; T/T, OR 2.55, 95% CI 1.36-4.80. In vitro, luciferase assay showed that rs354476 is a bona fide target for hsa-miR-125b-5p.

Conclusion(s): Nucleoporin GP210 is involved in endometriosis. Rs354476 polymorphism affects the regulation of NUP210 gene expression by altering the binding with hsa-miR-125b-5p, a microRNA already known as playing an important role for endometriosis. This provides the rationale for the observed increased risk of endometriosis in carriers of the variant allele.
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http://dx.doi.org/10.1016/j.fertnstert.2019.04.011DOI Listing
August 2019

Differentiating overlapping symptoms of vulvodynia and pudendal neuralgia.

Br J Pain 2019 Feb 15;13(1):54-58. Epub 2018 May 15.

Department of Orthopaedics and Traumatology, University Hospital of Siena, Siena, Italy.

Context: Vulvodynia is defined as a chronic vulvar pain non-associated with infectious, inflammatory, neoplastic or hormonal disorders.

Objectives: To present a case demonstrating the difficulty in assessing concomitant disease in vulvodynia.

Methods: A 26-year-old woman, presented with persistent vulvodynia. She received oral and topical medications and behavioural interventions to lessen sexual pain and restore sexuality. As sexual pain decreased, the patient reported symptoms previously not mentioned: continuous, intense periclitoral pain and numbness at the perineum when sitting for a long time. These new symptoms suggest the involvement of the peripheral neural system. The physical evaluation confirmed right-side pelvic distortion, and pathological increase in lumbar lordosis, which caused neuralgia radiating to the external genitalia and perineum, and overlapping with sexual pain. After diagnosing pudendal neuralgia according to the Nantes criteria, physical treatment and relaxation exercises to de-contract the spine were added to the vulvodynia regimen.

Results: During treatment, vulvodynia was sometimes present but never unbearable, allowing satisfactory sex. With physical therapy, the symptoms of pudendal neuralgia decreased.

Conclusion: Differentiating the presence of two conditions with overlapping symptoms is difficult because the vestibular pain had shadowed pudendal neuralgia symptoms at initial assessment. Syndromes of chronic pain tend to associate with each other and one syndrome may shadow symptoms of the concomitant condition affecting adjacent anatomical areas. Only the accurate identification of all the syndromes involved allows adopting the correct treatment.
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http://dx.doi.org/10.1177/2049463718776692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327350PMC
February 2019

Activin A in Mammalian Physiology.

Physiol Rev 2019 01;99(1):739-780

Department of Morphology, Universidade Federal de Minas Gerais , Belo Horizonte , Brazil ; Department of Experimental and Clinical Medicine, Università Politecnica delle Marche , Ancona , Italy ; Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais , Belo Horizonte , Brazil ; Department of Molecular and Developmental Medicine, Obstetrics and Gynecological Clinic, University of Siena , Siena , Italy ; and Department of Biomedical, Experimental and Clinical Sciences, Division of Obstetrics and Gynecology, University of Florence, Careggi University Hospital , Florence , Italy.

Activins are dimeric glycoproteins belonging to the transforming growth factor beta superfamily and resulting from the assembly of two beta subunits, which may also be combined with alpha subunits to form inhibins. Activins were discovered in 1986 following the isolation of inhibins from porcine follicular fluid, and were characterized as ovarian hormones that stimulate follicle stimulating hormone (FSH) release by the pituitary gland. In particular, activin A was shown to be the isoform of greater physiological importance in humans. The current understanding of activin A surpasses the reproductive system and allows its classification as a hormone, a growth factor, and a cytokine. In more than 30 yr of intense research, activin A was localized in female and male reproductive organs but also in other organs and systems as diverse as the brain, liver, lung, bone, and gut. Moreover, its roles include embryonic differentiation, trophoblast invasion of the uterine wall in early pregnancy, and fetal/neonate brain protection in hypoxic conditions. It is now recognized that activin A overexpression may be either cytostatic or mitogenic, depending on the cell type, with important implications for tumor biology. Activin A also regulates bone formation and regeneration, enhances joint inflammation in rheumatoid arthritis, and triggers pathogenic mechanisms in the respiratory system. In this 30-yr review, we analyze the evidence for physiological roles of activin A and the potential use of activin agonists and antagonists as therapeutic agents.
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http://dx.doi.org/10.1152/physrev.00002.2018DOI Listing
January 2019

Overweight and lower age at menarche: evidence from the Italian HBSC cross-sectional survey.

BMC Womens Health 2018 10 19;18(1):168. Epub 2018 Oct 19.

Department of Molecular and Developmental Medicine University of Siena, Siena, Italy.

Background: A unique standardized national dataset on adolescent girls (21 regions) participating in the Italian Health Behaviour in School-aged Children Study (HBSC) was used to investigate the correlation between body mass index (BMI) and age at menarche.

Methods: Two independent nationally representative survey datasets: one on 15-year-olds (n = 6907, in 21 regions, year 2013/2014) and one on 11-year-olds (n = 10,128, in 20 regions, year 2009/2010) were analysed. The survey instrument was a self-report questionnaire. Median age at menarche and 95% confidence intervals (CIs) were estimated by means of Kaplan-Meier analysis. Hierarchical models were used to assess the relationship between BMI and age at menarche (months). "Region-level obesity" was measured as the prevalence of overweight/obesity (%) in each region.

Results: Region-level median age at menarche ranged between 12 years/3 months and 13 years/4 months. Region-level prevalence of overweight among 15-year-old girls ranged between 4 and 19%. Age at menarche was inversely associated with individual BMI (unstandardized regression coefficient beta = - 0.70; 95% CI, - 0.84 to - 0.56). Individual- and class-level measures of BMI accounted for 50% of the region-level variance in age at menarche.

Conclusions: The results show that overweight in childhood is in relation with the early puberty in girls. Future surveys may take into account this report to clarify if overweight is the cause or consequence of early menarche.
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http://dx.doi.org/10.1186/s12905-018-0659-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194651PMC
October 2018

The sex life of women surviving breast cancer.

Gynecol Endocrinol 2018 Oct 27;34(10):821-825. Epub 2018 Apr 27.

a Division of Obstetrics and Gynecology, Department of Molecular and Developmental Medicine , University of Siena , Siena , Italy.

The diagnosis of breast cancer elicits diverse emotional responses in patients and partners. Surviving cancer has raised new needs and caretakers must understand the medical and psychological latent effects of oncology therapy. Improving patients' well-being is crucial as 19 million survivors are expected in the next decade in the United States alone. In general, sexuality contributes to one's well-being but when it is disrupted by the occurrence of cancer, women withdraw emotionally, no longer feel desirable due to esthetic damage, and become overwhelmed by the thought of sex. Alopecia and mastectomy elicit feelings of unattractiveness affecting even some women with nipple sparing mastectomy. Couples who share the psychological distress of experiencing cancer should be logically included in survivorship interventions. Hence, any support offered to the couple improves their ability to cope significantly. Treatments causing premature ovarian failure as well as adjuvant endocrine treatments deepen the effects of hypo-estrogenism on the genital modifications of arousal. Sexual rehabilitation with vaginal dilators and sensate focus exercises help to lessen pain, and reduce the couple's anxiety toward sex. In conclusion, caregivers must realize that surviving women are often reluctant to voice their needs, thus, efficient interventions must be available to everyone.
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http://dx.doi.org/10.1080/09513590.2018.1467401DOI Listing
October 2018

Role of medical therapy in the management of uterine adenomyosis.

Fertil Steril 2018 03;109(3):398-405

Department of Experimental, Clinical and Biomedical Sciences, University of Florence, Obstetrics and Gynecology, Careggi University Hospital, Florence, Italy. Electronic address:

Adenomyosis is a benign uterine condition affecting women at various ages with different symptoms. The management of these patients is still controversial. Few clinical studies focusing on medical or surgical treatment for adenomyosis have been performed. No drug is currently labelled for adenomyosis and there are no specific guidelines to follow for the best management. Anyhow, medical treatments are effective in improving symptoms (pain, abnormal uterine bleeding and infertility). The rationale for using medical treatment is based on the pathogenetic mechanisms of adenomyosis: sex steroid hormones aberrations, impaired apoptosis, and increased inflammation. Several nonhormonal (i.e., nonsteroidal anti-inflammatory drugs) and hormonal treatments (i.e., progestins, oral contraceptives, gonadotropin-releasing hormone analogues) are currently used off-label to control pain symptoms and abnormal uterine bleeding in adenomyosis. Gonadotropin-releasing hormone analogues are indicated before fertility treatments to improve the chances of pregnancy in infertile women with adenomyosis. An antiproliferative and anti-inflammatory effect of progestins, such as dienogest, danazol and norethindrone acetate, suggests their use in medical management of adenomyosis mainly to control pain symptoms. On the other hand, the intrauterine device releasing levonorgestrel resulted is extremely effective in resolving abnormal uterine bleeding and reducing uterine volume in a long-term management plan. Based on new findings on pathogenetic mechanisms, new drugs are under development for the treatment of adenomyosis, such as selective progesterone receptor modulators, aromatase inhibitors, valproic acid, and anti-platelets therapy.
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http://dx.doi.org/10.1016/j.fertnstert.2018.01.013DOI Listing
March 2018

Dermoscopic and reflectance confocal microscopy features of two cases of vulvar basal cell carcinoma.

Dermatol Pract Concept 2018 Jan 31;8(1):68-71. Epub 2018 Jan 31.

Department of Medical, Surgical and Neuro-Sciences, Dermatology Unit, University of Siena, Siena, Italy.

Basal cell carcinoma (BCC) is the most common malignant skin cancer. Its genital localization is rare, and the diagnosis in this site could be challenging. Here, we report two patients with vulvar BCC and describe their clinical, dermoscopic and in vivo and ex vivo reflectance confocal microscopic (RCM) features. Dermoscopy and RCM can be useful tools for helping the clinical diagnosis of vulvar BCC and for identifying the correct surgical margins.
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http://dx.doi.org/10.5826/dpc.0801a17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808379PMC
January 2018

GnRH antagonist does not prevent premature luteinization and ovulation in stimulated cycles with gonadotropins for IVF: two case reports.

Gynecol Endocrinol 2018 Mar 23;34(3):189-191. Epub 2017 Sep 23.

a Division of Obstetrics and Gynecology, Department of Molecular and Developmental Medicine , University of Siena , Siena , Italy.

The use of GnRH antagonists (GnRHant) is increasing in the ovarian stimulation protocol. Among several other benefits, GnRHant should prevent a premature luteinization and premature ovulation, the first described either as a 'reassuringly rare event' or 'frequent event', while the second as occurring more frequently in women with decreased ovarian reserve, advanced age and poor ovarian response. Two cases of associated premature luteinization and premature ovulation, during treatment with gonadotropins and GnRHant in IVF cycles, are here reported. In both cases, premature luteinization occurred and ovulation took place during ovarian stimulation protocols with exogenous gonadotropins and GnRHant, before reaching the criteria of hCG administration, regardless of the age of the patients and their ovarian reserve. Ovulation was documented by the disappearance of most of the developing follicles, by the transformation of endometrium from a triple line picture into a uniform hyper-echogenic image, by the presence of fluid in the pouch of Douglas, by the increase of progesterone plasma levels and the simultaneous reduction of estradiol plasma levels. This evidence can be important for a correct counseling with infertile patients in preparation for an IVF cycle.
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http://dx.doi.org/10.1080/09513590.2017.1380183DOI Listing
March 2018

Pelvic floor evaluation with transperineal ultrasound: a new approach.

Minerva Ginecol 2018 Feb 5;70(1):58-68. Epub 2017 Sep 5.

Unit of Obstetrics and Gynecology, Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy -

The increased life expectancy, the importance of the prevention in younger age and the role of the pelvic floor dysfunction not only in the disease of the third age, but also in the childbearing age, as the influence on the type of delivery, underline the importance of the evaluation of the pelvic floor. The evaluation of pelvic floor is generally clinical, but in the last 2 decades, the use of ultrasound has become a mainstream diagnostic tool in the investigation of female pelvic organ prolapse, urinary and fecal incontinence and defecation disorders, providing an immediate objective confirmation of findings obtained on clinical examination and filling some of the gaps of the urogynecological exam. The use of transabdominal ultrasound was the first developed, while the use of translabial, transrectal and transvaginal techniques started later. This review will focus on the use of transperineal ultrasound, including two-dimensional (2D), three-dimensional (3D) and 4D imaging, as a valuable and objective method in the urogynecological evaluation, allowing the assessment of the pelvic floor anatomy and its functions and dysfunctions, the choice of the right type of treatment and the analysis of the changes after surgical treatment and its complications. The ultrasound approach has become an important instrument for the prevention, but also for the analysis of the disease, and to understand the importance of the pelvic floor function in different period of life of a woman.
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http://dx.doi.org/10.23736/S0026-4784.17.04121-1DOI Listing
February 2018

Non-contraceptive benefits of intrauterine levonorgestrel administration: why not?

Gynecol Endocrinol 2017 Nov 6;33(11):822-829. Epub 2017 Jun 6.

a Obstetrics and Gynecology, Department of Molecular and Developmental Medicine , University of Siena , Siena , Italy.

Levonorgestrel intrauterine systems (LNG-IUS) represent a modern therapy for an array of preexisting gynecological conditions, though they were first marketed in Finland in 1990. However, there are countries in which their use is extremely limited by social and cultural factors. This manuscript describes the possible reasons for this misuse, taking in consideration the clinical noncontraceptive benefits of intrauterine levonorgestrel in routinary practice. Medical diseases in which LNG-IUS represent a treatment include abnormal uterine bleeding, iron-deficiency anemia, endometrial hyperplasia, uterine fibroids, adenomyosis, endometriosis, and coagulopathies. The advantage of reducing the need for more radical treatments such as surgery or hysterectomy is well demonstrated, with remarkable benefits for patients. However, in many countries, surgery is still used as a first-line treatment and there is a need to define who could benefit from a less invasive option. It seems clear that such a reduced use of LNG-IUS depends on factors that imply both patients and practitioners, and that the role of counseling is becoming a key component in the decision-making process to reach the ultimate goal of compliance.
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http://dx.doi.org/10.1080/09513590.2017.1334198DOI Listing
November 2017

Sexual pain in women: quality of sex life and marital relations.

Minerva Ginecol 2017 Aug 4;69(4):381-389. Epub 2017 Apr 4.

Department of Molecular and Developmental Medicine, Obstetrics and Gynecology, University of Siena, Siena, Italy -

Common gynecological and dermatological conditions resulting in sexual pain are often observed in gynecological practice and are easily diagnosed with visual observation and laboratory tests. The lower genital tract diseases we are referring to are vaginitis, vaginoses, dermatoses, hypoestrogenism and endometriosis. All of them affect the vaginal mucosa with diverse mechanisms, their effects lasting for only few days or many months. Furthermore, they change the women's sense of wellbeing sometimes significantly and for a long period. The conditions we mentioned above are recognized promptly with basic gynecological interventions but when burning or sharp pain occurs with light pressure (as in case of penetration attempts) without physical signs we must suspect the genitopelvic pain penetration disorder. This condition was defined for the first time in the Diagnostic and Statistical Manual of Mental Disorders-5 and its dimensions include difficulty or pain at penetration associated with fear, anxiety, and pelvic floor hypertonus. Pain is most often localized at the vulvar vestibule and described as burning, pressure, and itching. These dimensions are iconic of sexual pain associated with vulvodyina and vaginismus but are common also in fibromyalgia, a syndrome of widespread chronic pain of unknown origin; sexual pain in fibromyalgia is mostly attributed both to the joint pathology and to the lower sensitive threshold that are the pathognomonic signs of this condition. In our study we analyzed the characteristics of pain as reported for each disease to evaluate its influence on sexuality and marital relations.
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http://dx.doi.org/10.23736/S0026-4784.17.04054-0DOI Listing
August 2017

Macro-regional variation in attitudes toward and experiences of vulvar and vaginal atrophy among Italian post-menopausal women: a post hoc analysis of REVIVE survey data.

Gynecol Endocrinol 2017 May 21;33(5):389-394. Epub 2017 Feb 21.

g Department of Obstetrics and Gynaecology , University of Cagliari, University Hospital of Cagliari , Cagliari , Italy.

Italian participants in the European REVIVE survey reported that vaginal and vulvar atrophy (VVA) impaired various aspects of their lives, notably the ability to enjoy sex. The aim of the present study was to explore regional differences in knowledge, experiences, and treatment of VVA in the Italian REVIVE sample (n = 1000), which was analyzed according to region of residence. While many respondents were unfamiliar with the VVA condition, most could relate their VVA symptoms to the menopause. The rate of diagnosis of VVA was twice as high in Central Italy as in the North-East. For individual VVA symptoms, 25.4-41.6% of respondents judged that the symptom had worsened over time. There were no significant regional differences for symptoms in terms of reported rate, change in severity, impact on sexual activity, or health-care visits. Testosterone cream and OTC medication based on hyaluronic acid showed significant regional differences in lifetime rates of use. In Italy, there are modest regional differences in knowledge, diagnosis, and treatment of VVA, some of which may be explained by inter-regional differences in health care. Further efforts are needed to ensure that Italian women are properly informed about VVA and have access to appropriate health care and treatments.
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http://dx.doi.org/10.1080/09513590.2017.1284783DOI Listing
May 2017

Hormonal therapy for endometriosis: from molecular research to bedside.

Eur J Obstet Gynecol Reprod Biol 2017 Feb 27;209:61-66. Epub 2016 May 27.

Obstetrics and Gynecology, Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy. Electronic address:

Endometriotic lesions are associated with hormonal imbalance, including increased estrogen synthesis, metabolism and progesterone resistance. These hormonal changes cause increased proliferation, inflammation, pain and infertility. Hormonal imbalances are targets for treatment. Therapeutic strategies and innovations of hormonal drugs for endometriosis are increasing. Acting on estrogen receptors are hormonal drugs decreasing systemic and local estrogen synthesis (GnRH analogs, GnRH antagonists, Aromatase inhibitors) or estrogen activity (selective estrogen receptor modulators). The progesterone resistance is counteracted by progestins (Medroxyprogesterone acetate, Dienogest, Danazol, Levonorgestrel) or by Selective progesterone receptor modulators, a class of drugs under development. The future trend will be to define new drugs to use for prolonged period of time and with poor side effects considering endometriosis a chronic disease.
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http://dx.doi.org/10.1016/j.ejogrb.2016.05.032DOI Listing
February 2017

Attitudes and perceptions towards vulvar and vaginal atrophy in Italian post-menopausal women: Evidence from the European REVIVE survey.

Maturitas 2016 Sep 11;91:74-80. Epub 2016 Jun 11.

Department of Obstetrics and Gynaecology, University of Cagliari, University Hospital of Cagliari, Cagliari, Italy.

Objectives: To achieve a deeper understanding of the attitudes and perceptions of Italian post-menopausal women (PMW) regarding vulvo-vaginal atrophy (VVA).

Study Design: As part of the EU REVIVE study, an online survey was conducted in four European countries; the Italian arm comprised 1000 participants from representative regions of Italy.

Main Outcome Measures: The perceptions, experiences and needs of Italian PMW in relation to sexual and vaginal health.

Results: The most frequent VVA symptom was vaginal dryness (78%). Usually, the severity of symptoms was similar to or worse than when they first appeared. This was particularly true for dyspareunia, the most bothersome symptom (76%). VVA symptoms had a significant impact on Italian participants' ability to achieve pleasurable relations (74%) and spontaneity (70%). Although 75% of participants were still sexually active, their sex drive had been reduced by a third because of VVA. Women expected that doctors would start a discussion of menopausal symptoms and sexual health, but this was rarely the case (11%). Most women had been treated with a vaginal over-the-counter (OTC) product. Women who had discussed their condition with a physician were more likely (68%) to be under treatment for VVA than those who had not (36%). Low compliance was associated with symptom improvement (23%), not having annoying symptoms (22%), and the impossibility if restoring the vagina to normal (14%). Common reasons for treatment dissatisfaction were related to route of administration or discomfort. Lack of efficacy and fear of a hormone effect were perceived as the main limitations for OTC and local estrogen products, respectively.

Conclusions: Despite the commonness of VVA and its significant impact on quality of life, the condition remains underdiagnosed in Italy. Discussion of symptoms with doctors influences the diagnosis, and patients' satisfaction with available treatments is not high.
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http://dx.doi.org/10.1016/j.maturitas.2016.06.009DOI Listing
September 2016

Abnormal uterine bleeding unrelated to structural uterine abnormalities: management in the perimenopausal period.

Minerva Ginecol 2017 Feb 10;69(1):75-83. Epub 2016 Jun 10.

Department of Molecular and Developmental Medicine, Obstetrics and Gynecology, University of Siena, Siena, Italy -

Abnormal uterine bleeding (AUB) is one of the commonest health problems encountered by women and a frequent phenomenon during menopausal transition. The clinical management of AUB must follow a standardized classification system to obtain the better diagnostic pathway and the optimal therapy. The PALM-COEIN classification system has been approved by the International Federation of Gynecology and Obstetrics (FIGO); it recognizes structural causes of AUB, which can be measured visually with imaging techniques or histopathology, and non-structural entities such as coagulopathies, ovulatory dysfunctions, endometrial and iatrogenic causes and disorders not yet classified. In this review we aim to evaluate the management of nonstructural causes of AUB during the menopausal transition, when commonly women experience changes in menstrual bleeding patterns and unexpected bleedings which affect their quality of life.
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http://dx.doi.org/10.23736/S0026-4784.16.03944-7DOI Listing
February 2017

Diagnosis and management of symptoms associated with vulvovaginal atrophy: expert opinion on behalf of the Italian VVA study group.

Gynecol Endocrinol 2016 Aug 17;32(8):602-606. Epub 2016 May 17.

f Obstetrics and Gynecology, Department of Surgical Sciences, University of Cagliari , AOU Cagliari , Italy.

Vulvovaginal atrophy (VVA) is a chronic disorder that commonly occurs in postmenopausal women, whose symptoms are recognized among the most frequent and bothersome symptoms associated with menopause. The principal therapeutic goal in managing VVA is to relieve symptoms as well as to restore the vaginal environment to a healthy state. However, despite its high prevalence and negative impact on quality of life, VVA is underreported by women, underrecognized by gynecologists, and therefore, undertreated. In the light of the new development of treatment options for VVA, we here provide an updated expert opinion on the management of VVA. In particular, we strongly recommend that HCPs proactively start an open discussion with their postmenopausal patients about urogenital symptoms. Treatment should be started as early as the first symptoms of VVA occur and should be maintained over time, due to the chronicity of the conditions. Many treatment options are now available and therapy should be individualized, taking the woman's preference in consideration.
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http://dx.doi.org/10.1080/09513590.2016.1183627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5152549PMC
August 2016

Office hysteroscopy: an update.

Minerva Ginecol 2016 Apr;68(2):124-5

Department of Molecular and Developmental Medicine, Obstetrics and Gynecology, University of Siena, Policlinico "Le Scotte", Siena, Italy -

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April 2016

Office hysteroscopy: an update.

Minerva Ginecol 2016 Mar 11. Epub 2016 Mar 11.

Department of Molecular and Developmental Medicine, Obstetrics & Gynecology, University of Siena, Policlinico "Le Scotte", Siena, Italy -

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March 2016

Modern operative hysteroscopy.

Minerva Ginecol 2016 Apr 1;68(2):126-32. Epub 2016 Mar 1.

Department of Molecular and Developmental Medicine, Obstetrics and Gynecology, University of Siena, Siena, Italy -

Hysteroscopy is an endoscopic surgical procedure that has become an important tool to evaluate intrauterine pathology. It offers a direct visualization of the entire uterine cavity and provides the possibility of performing biopsy of suspected lesions that can be missed by dilatation and curettage (D&C). In most cases, the intrauterine pathologies can be diagnosed and treated at the same setting as office hysteroscopy ("see and treat approach"). For example, endometrial polyps can be diagnosed and removed; similarly, intrauterine adhesions can be liberated in the outpatient setting without the need for an operating theatre. Today, many hysteroscopic procedures can be performed in the office or outpatient setting. This is due to the feasibility of operative hysteroscopy using saline as a distending medium, the vaginoscopic approach of hysteroscopy and the availability of mini-hysteroscopic endoscopes. There is good evidence to suggest that hysteroscopy in an ambulatory setting is preferable for the patient, and that it avoids complications, allows a quicker recovery time and lowers cost. Advances in technology have led to miniaturization of high-definition hysteroscopes without compromising optical performance, thereby making hysteroscopy a simple, safe and well-tolerated office procedure. The new surgical technology such as bipolar electrosurgery, endometrial ablation devices, hysteroscopic sterilization, and morcellators has revolutionized this surgical modality. The modern development of hysteroscopy completely transformed the approach to the uterine intracavitary pathologies moving from a blind procedure under general anesthesia to an outpatient procedure performed under direct visualization, offering therapeutic and irreplaceable possibilities of treatment that should belong to every modern gynecologist.
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April 2016

Adenomyosis: What the Patient Needs.

J Minim Invasive Gynecol 2016 May-Jun;23(4):476-88. Epub 2016 Jan 6.

University of Tor Vergata, Rome, Italy.

A panel of experts in the field of endometriosis expressed their opinions on management options in a 28-year-old patient, attempting pregnancy for 1 year, with severe cyclic pelvic pain and with clinical examination and imaging techniques suggestive of adenomyosis. Many questions this paradigmatic patient may pose to the clinician are addressed, and all clinical scenarios are discussed. A decision algorithm derived from this discussion is also proposed.
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http://dx.doi.org/10.1016/j.jmig.2015.12.017DOI Listing
June 2017