Neuroendocrine disturbances in women with functional hypothalamic amenorrhea: an update and future directions.

Functional hypothalamic amenorrhea (FHA) is one of the most common causes of both primary and secondary amenorrhea in women of reproductive age. It is characterized by chronic anovulation and the absence of menses that appear as a result of stressors such as eating disorders, excessive exercise, or psychological distress. FHA is presumed to be a functional disruption in the pulsatile secretion of hypothalamic gonadotropin-releasing hormone, which in turn impairs the release of gonadotropin. Hypoestrogenism is observed due to the absence of ovarian follicle recruitment. Numerous neurotransmitters have been identified which play an important role in the regulation of the hypothalamic-pituitary-ovarian axis and of which the impairment would contribute to developing FHA. In this review we summarize the most recent advances in the identification of contributing neuroendocrine disturbances and relevant contributors to the development of FHA.

PCOS Physiopathology and Vitamin D Deficiency: Biological Insights and Perspectives for Treatment.

Recent literature has stressed the importance of vitamin D (VD) in polycystic ovary syndrome (PCOS). Women with PCOS are deficient in VD, particularly those with a higher weight. Hypovitaminosis is a risk factor for glucose intolerance, and reduced levels of VD is associated with insulin resistance and increased diabetes risk. Since women with PCOS and hirsutism seem to have lower levels of VD than women with PCOS without hirsutism, a correlation between VD deficiency and hyperandrogenism may be suggested. Interestingly, VD is crucial for many human physiological functions, including to counteract inflammation and oxidative stress. Some studies evaluated effects of VD supplementation on glucose homeostasis variables, hormonal status, lipid concentrations, and biomarkers of inflammation and oxidative stress among VD-deficient women. Moreover, VD has been shown to play a role in egg quality and fertility. This review aims to show the relationship between VD and the endocrine and metabolic profile of PCOS patients, as well as its implications for their fertility. The supplement of VD to the common therapy can lead to an improvement of the insulin resistance and lipid metabolism, a reduction of circulating androgens, as well as a better response to the induction of ovulation in PCOS women.

From diagnosis to treatment of androgen-secreting ovarian tumors: a practical approach.

About 5% of all ovarian tumors develop some form of hormonal activity. Only 1% of ovarian tumors will secrete androgens causing clinical hyperandrogenism. Most androgen-secreting neoplasms (ASN) derive from sex cord or stroma cells of the ovary and may affect both premenopausal and postmenopausal women. Typically, a patient will present reporting symptoms of rapidly increasing hyperandrogenization such as: hirsutism, acne, frontal/male pattern balding, and in severe cases even virilization. Sertoli-Leydig Cell Tumors are the most frequent ASN and constitute about 0.5% of all ovarian neoplasms. Typically affecting women under 30 years of age, these tumors are usually unilateral and benign. They are also the most common tumor in postmenopausal women suffering with hyperandrogenism. Other tumors originating from the sex-cord stroma are also known to develop in this population, but the incidence of these is much lower. Approaching suspected hyperandrogenemia and its related symptoms in a clinical setting can be a significant diagnostic challenge. When evaluating a patient for hyperandrogenism, it is important to assess the severity of symptoms but most of all it is critical to assess the time of onset and dynamics of symptom progression. Diagnostic tools including laboratory tests and imaging studies should also be engaged. When deriving a differential diagnosis for androgen-secreting ovarian tumors, adrenal gland tumors should be considered as well as typical endocrine pathologies including polycystic ovary syndrome, congenital adrenal hyperplasia, Cushing's disease, and acromegaly. Treatment options for an androgen-secreting ovarian tumors is mainly surgical, but in exceptional cases can involve pharmacotherapy alone.

Behavioral sex therapy and medications associated in the treatment of provoked vulvodynia: efficacy on pain and sexuality in three illustrative cases.

This paper tests the hypothesis that medications combined with behavioral sex therapy might lessen pain and restore sexuality in women with provoked vulvodynia. Three women affected by vulvodynia, otherwise healthy, in heterosexual relationship were treated at the Department of Obstetrics and Gynecology in a university hospital. In consecutive sessions of behavioral sex therapy, oral tricyclic antidepressants and vulvar applications of estrogen and hydrocortisone creams were prescribed in association with vaginal dilators and sensate focus exercises. The outcome supports the hypothesis that combined medications and sexual behavior interventions may be effective in lessening pain and restoring sexuality in women with provoked vulvodynia. The different dyadic balances observed in this small case series suggest how to best use this protocol. The positive results appear to be mostly due to behavioral sex therapy that was the new element added to the combination of pharmacological agents commonly used to treat provoked vulvodynia.

Sexual function and quality of life in women with endometriosis.

Endometriosis may exert a profound negative influence on the lives of individuals with the disorder, adversely affecting quality of life, participation in daily and social activities, physical and sexual functioning, relationships, educational and work productivity, mental health, and well-being. Symptoms of endometriosis represent a great source of stress and cause a substantial negative impact on the psychological parameters, on the daily life and on the physical functioning of patients. The impact of endometriosis on work attendance has very significant economic consequences, as lost productivity has an associated cost, as do career changes resulting from a decline in education due to symptoms. Endometriosis is a pathology that affects all aspects of women's lives and that thus, it must be treated with a multidisciplinary vision that includes not only a medical approach but also psychological, work, and economic support. In this specific long-term vision of patient-centered endometriosis care, aspects of quality of life and sexual health play a key role and should always be evaluated with any patient as part of a multidisciplinary management.

Extracellular matrix remodeling and inflammatory pathway in human endometrium: insights from uterine leiomyomas.

OBJECTIVE: To compare the expression profiles of matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of matrix metalloproteinases, TIMPs) in the endometrium of women with and without type 3 leiomyomas and to understand their relationship with inflammatory status. DESIGN: Molecular and in silico studies. SETTING: University hospital. PATIENT(S): Patients with type 3 leiomyomas ranging from 3 to 10 cm in diameter (n = 18) and control age-matched women undergoing surgery for ovarian cysts (n = 18) who underwent endometrial biopsies. INTERVENTION(S): Endometrial biopsies. MAIN OUTCOME MEASURE(S): To evaluate the expression levels of MMPs and TIMPs in the endometrium, quantitative reverse transcriptase polymerase chain reaction and Western blot were performed. With the use of immunofluorescence analysis, the investigated proteins were localized in the tissues. The expression levels of inflammatory mediators such as IL-1ß, IL-6, IL-10, TGF, COX1, COX2, STAT3, and VEGF were evaluated by quantitative reverse transcriptase polymerase chain reaction, and their relationships were detected by the STRING approach. RESULT(S): The endometrium of women with type 3 leiomyomas exhibited differential expression of MMPs and TIMPs, particularly MMP2, MMP11, and MMP14, as well as different topographic distribution, suggesting that leiomyomas may influence the endometrial molecular profile. Significant decreases in IL-1ß, IL-6, and IL-10 expression, along with increases in COX1 and COX2, as well as VEGF, were highlighted. The STRING approach suggests that this altered gene expression profile may affect the Th17 cell differentiation pathway. CONCLUSION(S): The differential expression and localization of MMPs and TIMPs observed in women with type 3 leiomyomas, along with the reported derangement in the expression of key molecules involved in the inflammatory pathway, may contribute to changes in endometrial receptivity in these patients.

Role of medical treatment of endometriosis.

Endometriosis is a chronic benign disease that affects women of reproductive age. Medical therapy is often the first line of management for women with endometriosis in order to ameliorate symptoms or to prevent post-surgical disease recurrence. Currently, there are several medical options for the management of patients with endometriosis and long-term treatments should balance clinical efficacy (controlling pain symptoms and preventing recurrence of disease after surgery) with an acceptable safety-profile. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of chronic inflammatory conditions, being efficacious in relieving primary dysmenorrhea. Combined oral contraceptives and progestins, available for multiple routes of administration, are commonly administered as first-line hormonal therapies. Several studies demonstrated that they succeed in improving pain symptoms in the majority of patients; moreover, they are well tolerated and not expensive. Gonadotropin-releasing hormone-agonists are prescribed when first line therapies are ineffective, not tolerated or contraindicated. Even if these drugs are efficacious in treating women not responding to COCs or progestins, they are not orally available and have a less favorable tolerability profile (needing an appropriate add-back therapy). Because few data are available on long-term efficacy and safety of aromatase inhibitors they should be reserved only for women with symptoms who are refractory to other treatments only in a research environment. Almost all of the currently available treatment options for endometriosis suppress ovarian function and are not curative. For this reason, research into new drugs is unsurprisingly demanding. Amongst the drugs currently under investigation, gonadotropin-releasing hormone antagonists have shown most promise, currently in late-stage clinical development. There is a number of potential future therapies currently tested only in vitro, in animal models of endometriosis or in early clinical studies with a small sample size. Further studies are necessary to conclude whether these treatments would be of value for the treatment of endometriosis.

Management of perimenopause disorders: hormonal treatment.

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.

Genitopelvic pain: retrospective evaluation of a multimodal treatment efficacy.

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.

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

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 (n = 15) and eutopic endometrium (n = 19) in OMA (n = 10) and DIE (n = 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 MMP3, MMP10, and TIMP2 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.

Is Stress a Cause or a Consequence of Endometriosis?

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.

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

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, p < .001, DNG; 18 ± 12, p < .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 (p < .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.

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

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 (p < .0005). There was no difference in personal care management after therapy. Modified FSFI showed a statistically significant improvement (p < .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.

Neonatal outcome in pregnancy hypotiroidee women.

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.

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

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.

Increased expression of neurogenic factors in uterine fibroids.

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.

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

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 ß-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.

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

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.