Hipoteza paradoksu estrogenowego

Epidemiological and observational studies suggest that oestrogens, when used as hormonal therapy in post-menopausal women, can increase the risk of breast cancer if used long term. However, more recent data suggest that short-term use in sub-groups of post-menopausal women significantly decreases the risk of breast cancer. This beneficial effect is also observed when high-dose oestrogen is administered to post-menopausal women with breast cancer to cause tumour regression, a phenomenon which commonly occurs. We consider these divergent responses to oestrogen to represent a "paradox". Data from our own and other investigative groups suggest a hypothesis to explain this paradox. Deprivation of oestradiol in model systems causes cells to adapt and to undergo apoptosis in response to oestrogen. This occurs through the Fas/Fas ligand death receptor pathway and through alterations in apoptotic mechanisms mediated by mitochondria. This process of programmed cell death may explain the regression of established breast cancer with oestrogen administration and the diminution in the rate of new breast cancer diagnoses recently reported. Our hypothesis is based upon pathological data indicating the presence of a "reservoir" of undiagnosed breast cancer in the population of women who would be starting on oestrogens as menopausal hormonal therapy. The long-term increased risk of breast cancer may then reflect different mechanisms. Oestrogens can cause mutations through enhancement of the rate of cell division and concomitantly the error rate in DNA replication. In addition, oestrogens can be metabolised to directly genotoxic compounds. These carcinogenic processes take much longer, since a number of mutations must accumulate before resulting in breast cancer. These hypotheses regarding oestrogen-induced apoptosis in the short term and carcinogenesis in the long term now require rigorous verification but would serve to explain the "oestrogen paradox". (Pol J Endocrinol 2007; 58 (3): 222-227)Badania epidemiologiczne i obserwacyjne sugerują, że estrogeny stosowane przez długi okres u kobiet w ramach hormonalnej terapii zastępczej, mogą zwiększać ryzyko wystąpienia raka piersi. Jednak ostatnie dane wskazują, że estrogeny stosowane krótko w podgrupie kobiet w okresie pomenopauzalnym, mogą to ryzyko istotnie zmniejszać. Ten sam korzystny efekt obserwowano również podczas podawania wysokich dawek estrogenów kobietom z rakiem piersi znajdującym się w okresie pomenopauzalnym, powodując regresję guza nowotworowego. Autorzy rozważyli odmienne wzorce reakcji na podane estrogeny. Zjawisko to można nazwać mianem paradoksu. Dane własne autorów oraz innych zespołów badawczych sugerują hipotezę, która mogłaby tłumaczyć powyższy "paradoks". W układzie modelowym deprywacja wpływu estradiolu powoduje, że komórki adaptują się i rozpoczynają proces apoptozy w odpowiedzi na działanie estrogenów. Zjawisko to przebiega poprzez receptor ścieżki śmierci dla liganda Fas/Fas oraz poprzez modyfikację mechanizmów apoptotycznych pośredniczonych przez mitochondria. Opisany powyżej proces programowanej śmierci komórek może tłumaczyć zarówno zjawisko regresji istniejącego już raka piersi po podaniu estrogenów, jak również opisywane ostatnio zmniejszenie częstości wykrywania nowych przypadków raka piersi. Hipoteza ta bazuje na danych wskazujących na istnienie w populacji dużej grupy kobiet, u których rak piersi pozostaje niezdiagnozowany, a które dopiero zaczną stosować estrogeny w ramach hormonalnej terapii zastępczej w okresie pomenopauzalnym. Obserwowany po dłuższym czasie wzrost częstości zachorowań na raka piersi u kobiet stosujących estrogeny, musi odzwierciedlać inny mechanizm działania tych związków. Estrogeny mogą powodować mutacje poprzez wzrost wskaźnika częstości podziałów komórkioraz następczego wzrostu liczby błędów podczas replikacji DNA. Ponadto estrogeny mogą zostać metabolizowane bezpośrednio do związków genotoksycznych. Opisane powyżej procesy karcynogenezy wymagają dłuższego czasu, ponieważ warunkiem koniecznym dla rozwoju raka piersi jest kumulacja wielu mutacji. Powyższa hipoteza dotycząca indukowanej apoptozy poprzez podawane w krótkim okresie czasu estrogenów oraz karcynogenezy spowodowanej podawaniem tych samych związków przez dłuższy czas wymaga ścisłej weryfikacji, jednak stara się wyjaśnić zjawisko "paradoksu estrogenowego". (Endokrynol Pol 2007; 58 (3): 222-227

Automated estimation of diploid and tetraploid nuclei with an electronic particle counter

1. 1. A method of counting and sizing nuclei by an electronic particle counter is described and evaluated.2. 2. Nuclei are separated into diploid and tetraploid classes by continuous density gradient sedimentation and DNA and RNA values per nucleus are reported.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31967/1/0000009.pd

Managing menopausal symptoms and associated clinical issues in breast cancer survivors

Objective: Review evidence to guide management of menopausal signs and symptoms in women after breast cancer and make recommendations accordingly. Evidence: Randomized controlled clinical trials, observational studies, evidence-based guidelines, and expert opinion from professional societies. Background: Symptoms and clinical problems associated with estrogen depletion—sleep disorders, vulvovaginal atrophy (VVA), vasomotor symptoms (VMS), mood changes, depressive symptoms, cardiovascular disease, osteopenia, and osteoporosis—confront the estimated 9.3 million breast cancer survivors globally. Recommendations: Following breast cancer, women should not generally be treated with menopausal hormone therapy or tibolone but should optimize lifestyle. Women with moderate to severe symptoms may benefit from mind–brain behavior or nonhormone, pharmacologic therapy. The selective serotonin/noradrenaline reuptake inhibitors and gabapentenoid agents improve VMS and quality of life. For osteoporosis, nonhormonal agents are available. Treatment of VVA remains an area of unmet need. Low-dose vaginal estrogen is absorbed in small amounts with blood levels remaining within the normal postmenopausal range but could potentially stimulate occult breast cancer cells, and although poorly studied, is not generally advised, particularly for those on aromatase inhibitors. Intravaginal dehydroepiandrosterone and oral ospemiphene have been approved to treat dyspareunia, but safety after breast cancer has not been established. Vaginal laser therapy is being used for VVA but efficacy from sham-controlled studies is lacking. Therapies undergoing development include lasofoxifene, neurokinin B inhibitors, stellate ganglion blockade, vaginal testosterone, and estetrol. Conclusions: Nonhormone options and therapies are available for treatment of estrogen depletion symptoms and clinical problems after a diagnosis of breast cancer. Individualization of treatment is essential

Treatment of symptoms of the menopause: an endocrine society clinical practice guideline

Objective: The objective of this document is to generate a practice guideline for the management and treatment of symptoms of the menopause. Participants: The Treatment of Symptoms of the Menopause Task Force included six experts, a methodologist, and a medical writer, all appointed by The Endocrine Society. Evidence: The Task Force developed this evidenced-based guideline using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned three systematic reviews of published data and considered several other existing meta-analyses and trials. Consensus Process: Multiple e-mail communications, conference calls, and one face-to-face meeting determined consensus. Committees of The Endocrine Society, representatives from endorsing societies, and members of The Endocrine Society reviewed and commented on the drafts of the guidelines. The Australasian Menopause Society, the British Menopause Society, European Menopause and Andropause Society, the European Society of Endocrinology, and the International Menopause Society (co-sponsors of the guideline) reviewed and commented on the draft. Conclusions: Menopausal hormone therapy (MHT) is the most effective treatment for vasomotor symptoms and other symptoms of the climacteric. Benefits may exceed risks for the majority of symptomatic postmenopausal women who are under age 60 or under 10 years since the onset of menopause. Health care professionals should individualize therapy based on clinical factors and patient preference. They should screen women before initiating MHT for cardiovascular and breast cancer risk and recommend the most appropriate therapy depending on risk/benefit considerations. Current evidence does not justify the use of MHT to prevent coronary heart disease, breast cancer, or dementia. Other options are available for those with vasomotor symptoms who prefer not to use MHT or who have contraindications because these patients should not use MHT. Low-dose vaginal estrogen and ospemifene provide effective therapy for the genitourinary syndrome of menopause, and vaginal moisturizers and lubricants are available for those not choosing hormonal therapy. All postmenopausal women should embrace appropriate lifestyle measures

Studies on the estimation of deoxyribonucleic acid and ribonucleic acid in rat brain

A method for the estimation of DNA and RNA in rat brain is described. The principal modifications of preexisting methods involve initial lipid extraction with chloroform-methanol and continuous stirring during alkaline hydrolysis of RNA and acid extraction of DNA. Comparison of ultraviolet-absorptive methods, phosphate determination, and orcinol reaction for RNA, shows a greater degree of correspondence than has previously been reported for brain tissue. Also, a relatively high degre of reproducibility for each of the methods used is obtained with a two-wavelength ultraviolet method. In addition to chemical separation of DNA and RNA components suitable for isotopic studies, an intact lipid fraction is obtained without acid or heating steps.Intracranial injection of [3H]thymidine into young rats resulted in incorporation of as much as 10% of the injected dose into DNA in 2 h.The DNA per cell nucleus obtained from brain homogenates was found to be 6.4[middle dot]10-12 g. On this basis, there 5.5[middle dot]108 cells in the brain of a young adult rat.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32265/1/0000327.pd

Studies on the estimation of deoxyribonucleic acid and ribonucleic acid in rat brain

A method for the estimation of DNA and RNA in rat brain is described. The principal modifications of preexisting methods involve initial lipid extraction with chloroform-methanol and continuous stirring during alkaline hydrolysis of RNA and acid extraction of DNA. Comparison of ultraviolet-absorptive methods, phosphate determination, and orcinol reaction for RNA, shows a greater degree of correspondence than has previously been reported for brain tissue. Also, a relatively high degre of reproducibility for each of the methods used is obtained with a two-wavelength ultraviolet method. In addition to chemical separation of DNA and RNA components suitable for isotopic studies, an intact lipid fraction is obtained without acid or heating steps.Intracranial injection of [3H]thymidine into young rats resulted in incorporation of as much as 10% of the injected dose into DNA in 2 h.The DNA per cell nucleus obtained from brain homogenates was found to be 6.4[middle dot]10-12 g. On this basis, there 5.5[middle dot]108 cells in the brain of a young adult rat.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32264/1/0000326.pd

The production of a linear density gradient by means of a propertioning pump

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32032/1/0000075.pd

GONADOTROPHINS AND TESTOSTERONE IN THE XYY SYNDROME

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32715/1/0000082.pd