In the thicket of fears, doubts, and murky facts: some reflections on treatment modalities for endometriosis-associated pain.

Endometriosis-associated pain can be managed by either surgery or hormonal therapy. The final decision as to which treatment modality to take is based on efficacy and possible complications of different treatment modalities, risk of recurrence, and the patient's wishes and preferences. But in the thicket of fears, doubts, and murky facts, the choice may ultimately be the trade-off between irrational fears and ignorance versus scientific evidence. We elaborate some pros and cons of the two treatment modalities and highlight some notable downsides of hormonal therapy, in particular the possible yet unquantified risk of long-term hormonal therapy for malignant transformation, perhaps with the only exception of combined oral contraceptives. Thus, when discussing with patients, we advocate the approach of discussing the advantages and disadvantages of all treatment options in detail, accounting for the known pros and cons with a full understanding of the predictive irrationality of human beings. For endometriosis-associated pain, surgery is definitely not a failure of medicine but, rather, a viable option, especially given the recently surfaced undercurrent of wariness and dissatisfaction with the current hormonal drugs among patients with endometriosis. Above all, there is a pressing need to fill the knowledge gap of perioperative interventions intended to reduce the risk of recurrence and to fulfill the demand for the development of safe and efficacious non-hormonal therapeutics.

Is hormonal therapy effective in advanced endometrial cancer? A systematic review and meta-analysis.

BACKGROUND: Hormonal therapy (HT) is used commonly in the treatment of advanced endometrial cancer (EC). However, a 2010 Cochrane Review did not show a survival benefit for HT. Here, we quantify its effects and explore the influence of clinico-pathologic factors and hormone receptor (HR) status on overall response rates (ORR). METHODS: A systematic search of electronic databases identified publications of HT in advanced EC. Data from individual studies reporting ORR, median progression-free (PFS) or overall survival (OS) were weighted by individual study sample size and pooled in a meta-analysis. Outcomes of estrogen (ER) and progesterone receptor (PgR) subgroups were collected. Studies of first- and second-line HT were analyzed independently. Mixed studies were included if subgroup data based on previous HT exposure were provided. Meta-regression was performed to evaluate the influence of clinico-pathologic factors on outcomes. RESULTS: Thirty-nine studies were included, with seven providing subgroup data based on HR status. First-line HT was associated with a mean ORR of 21.6% and clinical benefit rate (CBR) of 36.7%. Median PFS and OS were 2.8 and 10.2months respectively. ORR was 20.4% in clinical trials and 25.3% in observational studies. Magnitude of ORR was lower in older age, adenosquamous histology and high grade. ORR was higher in ER+ (26.5%) and PgR+ (35.5%) disease, and lower in ER- (9.2%) or PgR- (12.1%) tumors. Second-line ORR was 18.5%. CBR was 35.8%, but was significantly associated with timing of stable disease assessments in first- and second-line. Meta-regression performed in mixed and second-line studies showed an association between previous HT and greater ORR (ß 0.561; p=0.024), suggesting potential confounding by indication (re-treatment of good responders to first-line HT). CONCLUSION: HT is associated with modest ORR in advanced EC, and is greatest in HR+ tumors. Response rates in second-line are likely dependent on response to previous HT.

Radiation-associated breast cancer and gonadal hormone exposure: a report from the Childhood Cancer Survivor Study.

BACKGROUND: The relationship between hormone exposure and breast cancer risk in women treated with chest radiotherapy for childhood cancer is uncertain. METHODS: Participants included 1108 females from the Childhood Cancer Survivor Study who were diagnosed with childhood cancer 1970-1986, treated with chest radiotherapy, and survived to ages ⩾20 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox models adjusted for chest radiation field, delivered dose, anthracycline exposure, and age at childhood cancer estimated risk. RESULTS: Among 195 women diagnosed with breast cancer, 102 tumours were oestrogen-receptor positive (ER+). Breast cancer risk increased with ⩾10 years of ovarian function after chest radiotherapy vs <10 years (HR=2.89, CI 1.56-5.53) and for radiotherapy given within 1 year of menarche vs >1 year from menarche (HR=1.80, CI 1.19-2.72). Risk decreased with decreasing age at menopause (Ptrend=0.014). Risk factors did not differ for ER+ breast cancer. Survivors with an age at menopause <20 years treated with hormone therapy had a lower breast cancer risk than premenopausal survivors (HR=0.47, CI 0.23-0.94). CONCLUSIONS: Endogenous hormones are key contributors to breast cancer observed among childhood cancer survivors. Hormone therapy given for premature ovarian insufficiency does not fully replace the function that endogenous hormones have in breast cancer development.

Effect of Gonadal Hormones on Neurotransmitters Implicated in the Pathophysiology of Obsessive-Compulsive Disorder: A Critical Review.

Obsessive-compulsive disorder (OCD) is a relatively common neuropsychiatric disorder affecting between 1.6 and 3.2% of the population. A number of studies have previously reported increased incidence of OCD, or exacerbation of preexisting symptoms in females during reproductive events. Since these periods are known to involve fluctuating levels of gonadal hormones, these steroids have been suggested to be involved in modulating the course of the disorder. However, to date, only a few studies have measured hormone levels and obsessive-compulsive (OC) symptoms concurrently; thus, direct evidence for this relationship is limited. In turn, investigations into neurotransmission in OC individuals have been more extensive, and have implicated the serotonergic, dopaminergic, and glutamatergic neurotransmitter systems in OCD pathology. There is evidence suggesting that reproductive hormones estrogens and progesterone can modulate neurotransmission in the aforementioned signaling pathways by regulating the expression of receptors and channels, as well as the synthesis and release of the neurotransmitter itself. Overall, estrogen and progesterone appear to enhance serotonin signaling, which has been associated with improved OC symptoms. The effect of the gonadal hormones in dopaminergic and glutamatergic signaling is much more variable, highlighting the need for further research in this field. The existing evidence shows that gonadal hormones can have profound impacts on neurotransmission in the brain, leading to the conclusion that the hormonal fluctuations during reproductive events are a plausible factor contributing to the change in OCD course during these times.

The Potential of Gonadal Hormone Signalling Pathways as Therapeutics for Dementia.

Dementia is an ever-expanding problem facing an ageing society. Currently, there is a sharp paucity of treatment strategies. It has long been known that sex hormones, namely 17ß-estradiol and testosterone, possess neuroprotective- and cognitive-enhancing qualities. However, certain lacunae in the knowledge underlying their molecular mechanisms have delayed their use as treatment strategies in dementia. With recent advancements in pharmacology and molecular biology, especially in the development of safer selective oestrogen receptor modulators and the recent discovery of the small-molecule brain-derived neurotrophic factor receptor agonist, 7,8-dihydroxyflavone, the exploitation of these signalling pathways for clinical use has become possible. This review aims to adumbrate the evidence and hurdles underscoring the use of sex hormones in the treatment of dementia as well as discussing some direction that is required to advance the translation of evidence into practise.

Sex hormones and oxytocin augmentation strategies in schizophrenia: A quantitative review.

INTRODUCTION: Sex differences in incidence, onset and course of schizophrenia suggest sex hormones play a protective role in the pathophysiology. Such a role is also proposed for oxytocin, another important regulator of reproduction function. Evidence on the efficacy of sex hormones and oxytocin in the treatment of schizophrenia is summarized. METHODS: Double-blind, placebo-controlled, randomized studies were included, examining augmentation with estrogens, selective estrogen receptor modulators (SERMs), testosterone, dehydroepiandrosterone (DHEA), pregnenolone, and oxytocin. Outcome measures were total symptom severity, positive and negative symptom subscores, and cognition. In meta-analyses, combined weighted effect sizes (Hedges' g) per hormone were calculated. RESULTS: Twenty-four studies were included, examining 1149 patients. Significant effects were found for estrogen action (k=10), regarding total symptoms (Hedges' g=0.63, p=0.001), positive (Hedges' g=0.42, p<0.001), and negative symptoms (Hedges' g=0.35, p=0.001). Subgroup analyses yielded significant results for estrogens in premenopausal women (k=6) for total, positive, and negative symptoms, and for the SERM raloxifene in postmenopausal women (k=3) for total and negative, but not positive symptoms. Testosterone augmentation in males (k=1) was beneficial only for negative symptoms (Hedges' g=0.82, p=0.027). No overall effects were found for DHEA (k=4), pregnenolone (k=4), and oxytocin (k=6). Results for cognition (k=12) were too diverse for meta-analyses, and inspection of these data showed no consistent benefit. CONCLUSIONS: Estrogens and SERMs could be effective augmentation strategies in the treatment of women with schizophrenia, although potential side effects, partially associated with longer duration use, should be taken into account. Future trials are needed to study long-term effects and effects on cognition.

Ovarian hormones and chronic pain: A comprehensive review.

Most chronic noncancer pain (CNCP) conditions are more common in women and have been reported to worsen, particularly during the peak reproductive years. This phenomenon suggests that ovarian hormones might play a role in modulating CNCP pain. To this end, we reviewed human literature aiming to assess the potential role of ovarian hormones in modulating the following CNCP conditions: musculoskeletal pain, migraine headache, temporal mandibular disorder, and pelvic pain. We found 50 relevant clinical studies, the majority of which demonstrated a correlation between hormone changes or treatments and pain intensity, threshold, or symptoms. Taken together, the findings suggest that changes in hormonal levels may well play a role in modulating the severity of CNCP conditions. However, the lack of consistency in study design, methodology, and interpretation of menstrual cycle phases impedes comparison between the studies. Thus, while the literature is highly suggestive of the role of ovarian hormones in modulating CNCP conditions, serious confounds impede a definitive understanding for most conditions except menstrual migraine and endometriosis. It may be that these inconsistencies and the resulting lack of clarity have contributed to the failure of hormonal effects being translated into medical practice for treatment of CNCP conditions.

Rare cases of disorders of sex development (DSD) in adolescents with female phenotype.

BACKGROUND: Disorders of sex development (DSD) belong to uncommon pathologies; in addition, there are especially rare forms, such are ovotesticular disorders (OT), Turner syndrome and early malignisation of intraabdominal located gonads in the cases of androgen insensitivity syndrome. OBJECTIVE: In this article we present four rare cases of DSD in female phenotype adolescents: two cases of ovotesticular DSD with 46,XX and 46,XY karyotypes; one familial case of androgen insensitivity syndrome (AIS) with early malignancy (19-year-old) of intra-abdominally-located testicle in older siblings, and a case of spontaneous menstruation in a patient with Turner syndrome and mosaic karyotype 45,X/47,XXX. Rare cases of DSD are connected with diagnostic and management difficulties and so description of each such case and collection of data in this field is very important from a scientific, as well as a practical, point of view. Determination of prognosis and adequate management of each individual patient are also essential. Study of this issue is especially sensitive in the case of adolescent patients in order to avoid physiological stress, to reduce health risks and to improve quality of life.

Effects of progesterone and testosterone on ICH-induced brain injury in rats.

Studies have shown that progesterone reduces brain injury, whereas testosterone increases lesion size after ischemic stroke. This study examined the effects of progesterone and testosterone on intracerebral hemorrhage (ICH)-induced brain injury. Male Sprague-Dawley rats received an injection of 100 µL autologous whole blood into the right basal ganglia. Progesterone (16 mg/kg), testosterone (15 mg/kg) or vehicle was given intraperitoneally 2 h after ICH. Behavioral tests were performed, and the rats were killed after 24 h for brain edema measurement. Perihematomal brain edema was reduced in progesterone-treated rats compared to vehicle-treated rats (p<0.05). Progesterone also improved functional outcome following ICH (p<0.05). Testosterone treatment did not affect perihematomal edema formation, but resulted in lower forelimb placing score (p<0.05). In conclusion, progesterone can reduce brain edema and improve functional outcome, whereas testosterone may have a deleterious effect after ICH in male rats.

Reproductive factors, exogenous female hormone use and colorectal cancer risk: the Japan Public Health Center-based Prospective Study.

Evidence for an association between reproductive factors, exogenous female hormone use, and colorectal cancer risk from previous epidemiological studies remains controversial and information from nonwestern populations is limited. We analyzed this association in the Japan Public Health Center-based Prospective Study, conducted in 48 511 Japanese women aged 40-69 years who responded to a self-administered questionnaire that included history of reproductive factors, exogenous female hormone use, and other factors. During a mean follow-up of 12 years, a total of 538 colorectal cancer cases were newly identified. Age at menarche, menopausal status, history of exogenous female hormone use, parity, number of births, age at first birth, history of breast feeding, and reproductive period (postmenopausal women only) were not associated with colorectal cancer. When colon and rectal cancer were, however, analyzed separately among all women, multivariate-adjusted hazard ratios (95% confidence intervals) for colon cancer for age at first birth of 23-25, 26-29, 30 years or more in comparison to that at 22 years or less were 0.84 (0.64-1.12), 0.73 (0.53-1.01), and 0.66 (0.41-1.09), respectively (P for trend=0.03). These results were strengthened for colon cancer when analysis was restricted to postmenopausal women (P for trend=0.01), but no association was seen in premenopausal women (P for trend=0.59). In contrast, no statistically significant association was found for rectal cancer. These findings suggest that late age at first birth is associated with a reduced risk of colon cancer in postmenopausal Japanese women.

The role of HER1-HER4 and EGFRvIII in hormone-refractory prostate cancer.

PURPOSE: The role of the type I receptor tyrosine kinase (HER) family in progression of prostate cancer is controversial. Breast cancer studies show that these receptors should be investigated as a family. The current study investigates expression of HER1-HER4 and EGFRvIII in matched hormone-sensitive and hormone-refractory prostate tumors. EXPERIMENTAL DESIGN: Immunohistochemical analysis was used to investigate protein expression of HER1-HER4, EGFRvIII, and phosphorylated Akt (pAkt) in matched hormone-sensitive and hormone-refractory prostate tumors. RESULTS: Surprisingly, high HER2 membrane expression in hormone-sensitive tumors was associated with an increased time to biochemical relapse (P = 0.0003), and this translated into longer overall survival (P = 0.0021). Consistent with other studies, HER4 membrane expression in hormone-sensitive tumors was associated with longer time to biochemical relapse (P = 0.042), and EGFRvIII membrane expression was associated with shorter time to biochemical relapse (P = 0.015). An increase in pAkt expression was associated with reduced survival (P = 0.0098). Multivariate analysis showed that HER2 was an independent positive predictive marker of time to relapse in hormone-sensitive prostate tumors (P = 0.014). In contrast, high HER2 expression in hormone-refractory tumors was associated with decreased time to death from biochemical relapse (P = 0.039), and EGFRvIII nuclear expression was associated with decreased time to death from biochemical relapse and decreased overall survival (P = 0.02 and P = 0.005). CONCLUSION: These results suggest that the HER family may have multiple roles in prostate cancer, and that expression of the proteins alone is insufficient to predict the biological response that they may elicit.