Activin A in Mammalian Physiology.

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.

Role of lateral suspension for the treatment of pelvic organ prolapse: a Delphi survey of expert panel.

INTRODUCTION AND HYPOTHESIS: Lateral suspension is an abdominal prosthetic surgical procedure used to correct apical prolapse. The procedure involves the placement of a T-shaped mesh on the anterior vaginal wall and on the isthmus or uterine cervix that is suspended laterally and posteriorly to the abdominal wall. Since its description in the late 90s, modifications of the technique have been described. So far, no consensus on the correct indications, safety, advantages, and disadvantages of this emerging procedure has been reached. METHODS: A modified Delphi process was used to build consensus within a group of 21 international surgeons who are experts in the performance of laparoscopic lateral suspension (LLS). The process was held with a first online round, where the experts expressed their level of agreement on 64 statements on indications, technical features, and other aspects of LLS. A subsequent re-discussion of statements where a threshold of agreement was not reached was held in presence. RESULTS: The Delphi process allowed the identification of several aspects of LLS that represented areas of agreement by the experts. The experts agreed that LLS is a safe and effective technique to correct apical and anterior prolapse. The experts highlighted several key technical aspects of the procedure, including clinical indications and surgical steps. CONCLUSIONS: This Delphi consensus provides valuable guidance and criteria for the use of LLS in the treatment of pelvic organ prolapse, based on expert opinion by large volume surgeons' experts in the performance of this innovative procedure.

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.

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.

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.

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.

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.

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.

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

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.

The sex life of women surviving breast cancer.

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.

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

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.

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

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.

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.

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.

Naproxen sodium decreases prostaglandins secretion from cultured human endometrial stromal cells modulating metabolizing enzymes mRNA expression.

Dysmenorrhea, defined as painful cramps occurring immediately before or during the menstrual period, is a common symptom of different gynecological diseases. An acute uterine inflammatory response driven by prostaglandins (PGs) is responsible for painful symptoms. Progesterone withdrawal is responsible for activation of cyclooxygenase (COX-2) enzyme and decrease of hydroxyprostaglandin dehydrogenase (HPDG) with consequent increased secretion of PGs secretion, inducing uterine contractility and pain. The most widely used drugs for the treatment of pelvic pain associated with menstrual cycle are non steroidal anti-inflammatory drugs (NSAIDs). The uterine site of action of these drugs is still not defined and the present study evaluated the effect of naproxen sodium in cultured human endometrial stromal cells (HESC) collected from healthy women. PGE2 release was measured by ELISA; COX-2 and HPDG mRNA expression were assessed by qRT-PCR. Naproxen sodium did not affect HESC vitality. Naproxen sodium significantly decreased PGE2 secretion (p < 0.01) and COX-2 mRNA expression (p < 0.01). TNF-α induced PGE2 release was reduced in presence of naproxen sodium (p < 0.05), in association with decreased COX-2 and increased HPDG mRNAs expression. Naproxen sodium decreases endometrial PGE2 release induced by inflammatory stimulus acting on endometrial COX-2 and HPDG expression, suggesting endometrial synthesis of prostaglandins as a possible target for reduction of uterine inflammatory mechanism in dysmenorrhea.

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

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.

Adenomyosis: What the Patient Needs.

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.

Expression, localization and control of activin A release from human umbilical vein endothelial cells.

Activin-A is a member of the TGFß superfamily found in maternal and umbilical cord blood throughout gestation. We investigated whether human umbilical vein endothelial cells (HUVEC) express activin-A in vivo and tested the effects of vasoactive (endothelin-1), pro-inflammatory (interferon-γ, interleukin-8) and anti-inflammatory (dexamethasone, urocortin) factors on activin-A release by isolated HUVEC in vitro. Activin ßA subunit protein and mRNA were strongly localized in the endothelial cells of umbilical veins and were also detectable in scattered cells of the cord connective tissue. Dimeric activin-A was detected in the HUVEC culture medium at picomolar concentrations. Activin-A release by HUVEC decreased after cell incubation with urocortin (p < 0.01), whereas no effect was observed with interleukin-8, interferon-γ, endothelin-1 or dexamethasone. In summary, activin-A is present in the human umbilical vein endothelium in vivo and is produced and released by isolated HUVEC. Activin-A secretion is inhibited in vitro by urocortin, a neuropeptide with predominantly anti-inflammatory action.

Mood disorders and quality of life in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) affects 5-10% of the population of women. The exact etiology of PCOS remains unclear, but it is believed to result from complex interactions between genetic, behavioral and environmental factors. The spectrum of its symptoms such as hirsutism, skin problems, obesity and finally infertility has a huge negative impact on the individuals' psychological and interpersonal functioning. PCOS symptoms can lead to significant deterioration in quality of life and be highly stressful negatively affecting psychological well-being and sexuality. Fear symptoms like palpitation, being out of breath and tension might be caused by many somatic diseases. Moreover, detection and continuous thinking about illness can lead to significant negative impact on individual functioning in society. PCOS may be a factor potentially favoring the occurrence of mood disorders and depression. Biological, social and psychological consequences of PCOS among women of reproductive age are opening a new perspective on management of women's health in these patients.