Estrogen for the Treatment and Prevention of Breast Cancer: A Tale of 2 Karnofsky Lectures.

ABSTRACT: In 1971, Sir Alexander Haddow et al. delivered the inaugural David A. Karnofsky lecture at the American Society for Clinical Oncology. This award was designated American Society for Clinical Oncology's highest, as he had used translational research to identify the first clinical therapy, that is, synthetic estrogens to treat breast cancer. His lecture was entitled "Thoughts on Chemical Therapy." For 40 years, high-dose synthetic estrogens were used as palliative therapy, for some advanced breast cancer patients 5 years following menopause. Mechanisms were unknown. Tamoxifen, a failed "morning-after pill," is an antiestrogen in estrogen receptor-positive breast cancer, which was subsequently used to treat all stages of breast cancer and to prevent breast cancer. In 2008, Jordan was selected to present the 38th Karnofsky lecture entitled: "The Paradoxical Action of Estrogen in Breast Cancer-Survival or Death?" Unexpectedly, through a study of acquired resistance to long-term tamoxifen therapy, estrogen-induced apoptosis in long-term estrogen-deprived breast cancer was deciphered in Jordan's laboratory. These data and the biological rules established under laboratory conditions provided molecular mechanisms to aid in the interpretation of the Women's Health initiative in the United States and the Million Women Study in the United Kingdom. In addition, by establishing laboratory models to understand mechanisms of estrogen-induced apoptosis, new estrogen derivatives were successfully evaluated in the laboratory and tested as candidates for women after the therapeutic failure of antiestrogenic strategies to treat breast cancer. For the future, the knowledge obtained about estrogen-induced apoptosis in cancer holds the promise of discovering new therapies to control or cure cancer in general.

Posttreatment Strategy Against Hypoxia and Ischemia Based on Selective Targeting of Nonnuclear Estrogen Receptors with PaPE-1.

Newly synthesized Pathway Preferential Estrogen-1 (PaPE-1) selectively activates membrane estrogen receptors (mERs), namely, mERα and mERß, and has been shown to evoke neuroprotection; however, its effectiveness in protecting brain tissue against hypoxia and ischemia has not been verified in a posttreatment paradigm. This is the first study showing that a 6-h delayed posttreatment with PaPE-1 inhibited hypoxia/ischemia-induced neuronal death, as indicated by neutral red uptake in mouse primary cell cultures in vitro. The effect was accompanied by substantial decreases in neurotoxicity and neurodegeneration in terms of LDH release and Fluoro-Jade C staining of damaged cells, respectively. The mechanisms of the neuroprotective action of PaPE-1 also involved apoptosis inhibition demonstrated by normalization of both mitochondrial membrane potential and expression levels of apoptosis-related genes and proteins such as Fas, Fasl, Bcl2, FAS, FASL, BCL2, BAX, and GSK3ß. Furthermore, PaPE-1-evoked neuroprotection was mediated through a reduction in ROS formation and restoration of cellular metabolic activity that had become dysregulated due to hypoxia and ischemia. These data provide evidence that targeting membrane non-GPER estrogen receptors with PaPE-1 is an effective therapy that protects brain neurons from hypoxic/ischemic damage, even when applied with a 6-h delay from injury onset.

The role of menopausal hormone therapy in the management of osteoporosis.

It is now 75 years since Fuller Albright published his observations on the causal relationship between menopausal estrogen deficiency and osteoporosis. He introduced the concept of menopausal hormone therapy (MHT) for the prevention of osteoporosis. Most of his remarkable observations have stood the test of time and scientific scrutiny. Unfortunately, the uptake of MHT for the prevention of osteoporosis and related fractures remains very low. This can be ascribed to several factors. The availability of new drugs, supported by randomized clinical trials, has increased therapeutic options and created the impression that all new drugs are better compared to MHT. Confusion exists as to the benefit/risk profile of menopausal hormone therapy, limitations on the age of initiation of treatment, limitations on the length of treatment, and the need for treatment in the young menopausal woman with low bone density.

Exposures to synthetic estrogens at different times during the life, and their effect on breast cancer risk.

Women are using estrogens for many purposes, such as to prevent pregnancy or miscarriage, or to treat menopausal symptoms. Estrogens also have been used to treat breast cancer which seems puzzling, since there is convincing evidence to support a link between high lifetime estrogen exposure and increased breast cancer risk. In this review, we discuss the findings that maternal exposure to the synthetic estrogen diethylstilbestrol during pregnancy increases breast cancer risk in both exposed mothers and their daughters. In addition, we review data regarding the use of estrogens in oral contraceptives and as postmenopausal hormone therapy and discuss the opposing effects on breast cancer risk based upon timing of exposure. We place particular emphasis on studies investigating how maternal estrogenic exposures during pregnancy increase breast cancer risk among daughters. New data suggest that these exposures induce epigenetic modifications in the mammary gland and germ cells, thereby causing an inheritable increase in breast cancer risk for multiple generations.

Neuroprotection with non-feminizing estrogen analogues: an overlooked possible therapeutic strategy.

Although many of the effects of estrogens on the brain are mediated through estrogen receptors (ERs), there is evidence that neuroprotective activity of estrogens can be mediated by non-ER mechanisms. Herein, we review the substantial evidence that estrogens neuroprotection is in large part non-ER mediated and describe in vitro and in vivo studies that support this conclusion. Also, we described our drug discovery strategy for capitalizing on enhancement in neuroprotection while at the same time, reducing ER binding of a group of synthetic non-feminizing estrogens. Finally, we offer evidence that part of the neuroprotection of these non-feminizing estrogens is due to enhancement in redox potential of the synthesized compounds.

Hormonal contraception and bone metabolism: a systematic review.

BACKGROUND: Although a large amount of studies in the literature evaluated the effects of hormonal contraception on bone, many questions remained still unclear, such as the effect of these therapies on fracture risk. STUDY DESIGN: We performed a systematic search of the published studies from January 1975 through January 2012 on the effects of hormonal contraceptives on bone metabolism. We analyzed the overall effect on bone mineral density (BMD) and on fracture risk of combined oral contraceptives (COCs), progestogen-only contraceptives, transdermal contraceptives and vaginal ring. RESULTS: COC therapy does not seem to exert any significant effect on BMD in the general population. In adolescents, the effects of COCs on BMD seem to be mainly determined by estrogen dose. The use of COCs in perimenopausal women seems to reduce bone demineralization and may significantly increase BMD even at a 20-mcg dose. Use of depot medroxyprogesterone acetate is associated with a decrease in BMD, although this decrease seems to be partially reversible after discontinuation. Data on other progestogen-only contraceptives, transdermal patch and vaginal ring are still limited, although it seems that these contraceptive methods do not exert any influence on BMD. CONCLUSIONS: Hormonal contraceptives do not seem to exert any significant effect on bone in the general population. However, other randomized controlled trials are needed to evaluate the effects on fracture risk since the data available are derived from studies having the effects on BMD as the primary end point, and BMD may not accurately reflect the real fracture risk.

Neuroprotective actions of estradiol and novel estrogen analogs in ischemia: translational implications.

This review highlights our investigations into the neuroprotective efficacy of estradiol and other estrogenic agents in a clinically relevant animal model of transient global ischemia, which causes selective, delayed death of hippocampal CA1 neurons and associated cognitive deficits. We find that estradiol rescues a significant number of CA1 pyramidal neurons that would otherwise die in response to global ischemia, and this is true when hormone is provided as a long-term pretreatment at physiological doses or as an acute treatment at the time of reperfusion. In addition to enhancing neuronal survival, both forms of estradiol treatment induce measurable cognitive benefit in young animals. Moreover, estradiol and estrogen analogs that do not bind classical nuclear estrogen receptors retain their neuroprotective efficacy in middle-aged females deprived of ovarian hormones for a prolonged duration (8weeks). Thus, non-feminizing estrogens may represent a new therapeutic approach for treating the neuronal damage associated with global ischemia.

The effect of synthetic genistein on menopause symptom management in healthy postmenopausal women: a multi-center, randomized, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy of synthetic genistein for reducing the frequency and severity of hot flushes. STUDY DESIGN: A 12 week randomized double-blind, placebo-controlled study in which 84 postmenopausal women received placebo or a single 30 mg dose of synthetic genistein. Outcome measures primary: percentage change in the number of daily hot flushes from pre-treatment to week 12. Secondary: duration and severity of daily hot flushes, Greene Climacteric Scale score, serum follicle stimulating hormone (FSH), 17ß-estradiol and endometrial thickness. RESULTS: Genistein supplemented subjects completing at least 4 weeks on trial (n=40) demonstrated a 51% reduction (9.4-4.7/day) in the number of hot flushes by week 12 compared to a 27% reduction in the placebo group (9.9-7.1/day) (p=0.026). Subjects in the genistein group also reported significantly fewer hot flushes per day (p=0.010) and a decrease in total duration of hot flushes per day (p=0.009) at week 12 versus placebo. Subjects on genistein (n=32) completing 12 weeks on trial demonstrated a 51% reduction (9.7-4.7/day) in the number of hot flushes by week 12 (p=0.049) compared to 30% reduction in the placebo group (9.8-7.0/day) and had fewer hot flushes per day and a decrease in total duration of hot flushes per day at week 12 compared to placebo (p=0.020 and p=0.017, respectively). There were no differences between groups in Greene Climacteric Scale, FSH, 17ß-estradiol, endometrial thickness or adverse events. CONCLUSIONS: The current study provides the first evidence that a single daily dose of 30 mg of synthetic genistein reduces hot flush frequency and duration.

The medicalisation of 'tall' girls: A discourse analysis of medical literature on the use of synthetic oestrogen to reduce female height.

Endocrine research in the 1930s increased and extended the use of sex hormones as medical therapies in an unprecedented way, especially for female ailments. In the 1950s the therapeutic use of sex hormones extended to the treatment of 'tall' girls. Ambiguity in the definition of the 'tall' girl, the arbitrary nature of the treatment decision, and diversity in the therapeutic regimes highlight the problematic nature of this medical practice. Using linguistic repertoires to study the political and ideological implications found in the patterned use of language, this paper reports on a discourse analysis of the medical literature on treatment of tall girls between the 1950s and 1990s, when this treatment was at its peak. Three linguistic repertoires emerged: the institutional authority of medicine to determine the 'abnormality' of tall stature in females; the clinical knowledge and experience in the diagnosis of medical risk associated with tall stature in women; and using hormones as cosmetic therapy to (re)produce femininity in tall girls. All three related to the maintenance of the cultural representations and social expectations of femininity. With no evidence of psychological harm associated with tall stature in women, and no long-term studies of either effectiveness or benefit, over five decades clinicians persuaded themselves and their patients that tall stature required therapeutic intervention. The treatment of tall girls with high dose oestrogen must be viewed as the medicalisation of a normal physical attribute adversely related to the social construction of gender.

Estrogen analogues: promising target for prevention and treatment of esophageal squamous cell carcinoma in high risk areas.

Esophageal cancer (EC) is one of the six most common cancers across the world. The striking 3-4: 1male predominance of esophageal squamous cell carcinoma (ESCC) has not yet been well explained. Our hypothesis is that the changes in level of estrogen and/or subtype of estrogen receptor (ER) may exert a protective factor in esophageal carcinogenesis and thus estrogen analogues may represent a promising target for prevention and treatment of ESCC. Several lines of evidence in a mouse ESCC model have suggested an inhibitory role of estrogen in ESCC growth and development. Consistent with this, our results showed that male and female counterparts from a high incidence area (HIA) for EC had significantly decreased serum estradiol compared to healthy controls from a low incidence area (LIA). Moreover, serum level of estradiol of ESCC patients from the HIA were significantly lower compared to healthy controls from both HIA and LIA. Numerous studies indicate that relatively low androgen level, high estrogen level (environmental and endogenous) and ratio alteration of sex hormones are important factors explaining decreased ESCC incidence. Both ERalpha and ERbeta are ligands to estradiol with different effects on transcription at activator protein-1 sites. Estrogen exerts a suppressive effect, mainly through ERalpha in ESCC, and an accelerative function, mainly through ERbeta. Our hypothesis suggests that administration of novel potent estrogen analogues might be an effective measure for prevention and treatment of ESCC in HIA.

[Effect of estrogens and liposomes on the course of the purulent wounds healing in elderly and senile patients].

The cytological changes dynamics during the process of the purulent wounds healing in elderly and senile patients using estrogens and liposomes in complex of treatment are adduced.

Female sexual function and dysfunction in the reproductive years: the influence of endogenous and exogenous sex hormones.

INTRODUCTION: Sexual function in women in the reproductive age years is under psychological, sociocultural, and relationship influences, as well as the influence of sex hormones. AIM: To examine the data relating to sexual function in women in the reproductive age group, particularly the influence of sex hormones. To examine, in particular, the influence of the menstrual cycle, pregnancy, the oral contraceptive pill and endogenous and exogenous testosterone. METHODS: Review of the literature on female sexual function, confining the search to the reproductive age range. RESULTS: Population studies of sexual function identify sexual disinterest as being the most common sexual complaint in premenopausal women. Most studies of menstrual cyclicity identify a periovulatory increase in sexual desire or activity. All prospective studies of sexuality in pregnancy document a decline in sexual function with progression of pregnancy. Studies of the influence of the oral contraceptive pill on sexual function are contradictory with most prospective controlled studies showing no deleterious effect. Studies of the influence of endogenous androgens on sexuality are also contradictory with one large cross-sectional study showing no correlation, but some case-controlled studies show low androgens in women with sexual dysfunction. Studies of testosterone therapy in premenopausal women are ambiguous, with no clear dose-response effect. CONCLUSIONS: Sexual disinterest is prevalent in premenopausal woman despite being hormone replete. The assessment of androgen contribution is hampered by the unreliability of the testosterone assay in the female range. Large cross-sectional and longitudinal studies have not identified a correlation between testosterone and sexual function in women. Sexual dysfunction in the premenopausal age range is common. Sex hormones have a modifying effect on sexual function but social influences and learned responses are as important. The role of testosterone requires further study.

GPR30: a novel therapeutic target in estrogen-related disease.

Estrogen is a crucial hormone in human physiology that regulates a multitude of biological processes. It is also an important target in many diseases such as cancer and skeletal, neurological and immunological conditions. The actions of estrogen have traditionally been ascribed to one of two closely related classical nuclear hormone receptors, ERalpha and ERbeta, which are best characterized for regulating gene expression. Recent studies have revealed the contribution of a novel estrogen receptor GPR30, which belongs to the family of seven-transmembrane G-protein-coupled receptors, to many of the rapid biological responses to estrogen. Many drugs, such as tamoxifen and fulvestrant, which seem to selectively inhibit the activities of the classical estrogen receptors, are in widespread clinical use. However, recent results indicate that these same drugs activate multiple cellular-signaling pathways via GPR30. Unraveling the pharmacological profiles and specificities of ERalpha, ERbeta and GPR30 will be vital for understanding not only the physiological roles of each receptor but also for the development of the next generation of receptor-specific drugs.

[Synthetic estrogens: some new pharmacological actions and mechanisms].

Many constitutional analogues of estrogen have been reported. In this review, the application, action(s), and mechanism(s) of clinically used synthetic estrogens are described. Estramustine and phosphestrol have been used for many years in the treatment of advanced prostate cancer. Estramustine phosphate is a prodrug that is rapidly on oral administration to the five metabolites, estramustine, estromustine, estradiol, estrone and anticancer drug, nitrogen mustards. Estramustine induces dose- and time-dependent metaphase arrest and breakdown of interphase microtubules. Raloxifene is a selective estrogen receptor modulator from the benzothiophene class that binds to the estrogen receptor and has estrogen-agonist effects on bone. Raloxifene has used in female patients with postmenopausal osteoporosis.

Combination therapy for osteoporosis: considerations and controversy.

Combination therapy, the simultaneous use of two pharmaceutical agents with the goal being reduction of fracture risk, is an area of substantial clinical interest. This paper summarizes the rationale, existing clinical trials data, and other considerations relevant to combination therapy for osteoporosis. Combinations of antiresorbers (eg, estrogen plus bisphosphonates) produce greater increases in bone mass than either treatment alone. Conversely, combining anabolic agents (parathyroid hormone) with bisphosphonates does not produce additive effects. None of the existing studies are large enough to determine whether combination treatment reduces fracture risk to a greater extent than use of a single agent. However, it is certain that combination treatment will increase cost and likely that it will increase side effects and reduce therapy adherence. Given the absence of demonstrated fracture reduction benefit, increased cost and likely increase in adverse events, combination therapy is not currently recommended.

Efficacy of tibolone and transdermal estrogen therapy on psychological symptoms in women following surgical menopause.

OBJECTIVE: This study investigated the efficacy of tibolone and transdermal estradiol therapy on menopausal and psychological symptoms in women following surgical menopause. METHOD: Seventy-five women who had undergone surgical menopause were randomized to a 6-month double-blind interventional study treatment with oral 2.5 mg/day tibolone, transdermal 3.9 mg/week estradiol or oral placebo. The patients were assessed using Kupperman's Scale, Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale (HARS) before and at the end of the 6 months of treatment. RESULT: Sixty-five subjects completed the study: 23 on tibolone, 21 on transdermal estradiol and 21 on placebo. At the end of the 6 months of therapy, highly significant improvements in menopausal symptoms, depression and anxiety scores were observed in both groups (tibolone and transdermal estradiol groups) as compared with baseline values (p<0.001). However, in the placebo group, there were no significant differences on changes from baseline to the end of treatment (p>0.05). CONCLUSION: These results suggest that tibolone and transdermal estradiol therapy significantly improve menopausal and psychological symptoms in women following surgical menopause.

Estrogen-like compounds for ischemic neuroprotection.

We have synthesized a library of estrogen analogues, including enantiomers of estradiol and A-ring substituted estrogens. These compounds have reduced or no binding to either estrogen receptor-alpha or estrogen receptor-beta, exhibit enhanced neuroprotective activity in in vitro models, and are potent in protecting brain tissue from cerebral ischemia/reperfusion injury. These potent, nonfeminizing estrogen analogues are prime candidates for use in stroke neuroprotection.

[Effect of nylestriol on bone remodeling in ovariectomized rats].

OBJECTIVE: To clarify the effects of nylestriol on microarchitecture and interleukin-6 (IL-6) mRNA expression in tibial bone in ovariectomized rats. METHODS: 30 female rats were randomly allocated into 3 groups: sham, OVX and nylestriol-treated group. Nylestriol-treated group were ovariectomized, then fed with nylestriol for 3 months and the bone mineral density (BMD) was measured in lumbar vertebra by dual energy x-ray absorptiometry. After sacrifice of the animal, bone histomorphometric parameters were measured to study the changes in bone microarchitecture, and RT-PCR was performed to detect the expression of IL-6 mRNA in bone tissue. RESULTS: BMD was significantly reduced, while IL-6 mRNA level elevated in the OVX group compared with the sham group. Static histomorphometric data showed that the trabecular bone volume, mean trabecular plate thickness and density were reduced while the mean trabecular plate space elevated remarkably in the OVX group in comparison with that in the sham group. As for dynamic parameters, trabecular osteoid surface, tetracyclin labeled surface and bone turnover rate were increased while osteoid maturation rate decreased significantly in the OVX group compared with the sham group. BMD, IL-6 mRNA expression and bone histomorphometric parameters were improved in nylestriol-treated rats. CONCLUSION: Nylestriol plays an important role in maintaining bone volume and improving bone microarchitecture by markedly inhibiting bone turnover and bone resorption, which might be to some degree attributed to reduced IL-6 expression.

Estrogen receptor subtypes alpha and beta contribute to neuroprotection and increased Bcl-2 expression in primary hippocampal neurons.

Estrogen receptor (ER) mediated neuroprotection has been demonstrated in both in vitro and in vivo model systems. However, the relative contribution by either ER subtype, ERalpha or ERbeta, to estrogen-induced neuroprotection remains unresolved. To address this question, we investigated the impact of selective ER agonists for either ERalpha, PPT, or ERbeta, DPN, to prevent neurodegeneration in cultured hippocampal neurons exposed to excitotoxic glutamate. Using three indicators of neuronal viability and survival, we demonstrated that both the ERalpha selective agonist PPT and the ERbeta selective agonist DPN protected hippocampal neurons against glutamate-induced cell death in a dose-dependent manner, with the maximal response occurring at 100 pM. Further analyses showed that both PPT and DPN enhanced Bcl-2 expression in hippocampal neurons, with an efficacy comparable to their neuroprotective capacity. Collectively, the present data indicate that activation of either ERalpha or ERbeta can promote neuroprotection in hippocampal neurons, suggesting that both receptor subtypes could be involved in estrogen neuroprotection. As ERbeta is highly expressed in the brain and has little or no expression in the breast or uterus, discovery and design of ERbeta selective molecules could provide a strategy for activating the beneficial effects of estrogen in the brain without activating untoward effects of estrogen in reproductive organs.