Estrogen Implants Research Articles

Effect of medial preoptic oestradiol implants on hypothalamic beta-endorphin concentration.

Twenty-four-day-old immature and cyclic female rats in metoestrus were ovariectomized and bilaterally implanted with oestradiol benzoate (OB) and cholesterol at a ratio of 1:360 or with cholesterol alone in the medial preoptic area (MPOA), or, for control, the hypothalamic dorsomedial nucleus. Estimation of beta-endorphin immunoreactivity in the ventromedial-arcuate-median eminence region at 6 and 3 days after implantation, respectively, revealed a significantly higher concentration in rats implanted with OB in the MPOA as compared to those implanted with cholesterol. OB implants placed in the dorsomedial nuclei were ineffective in this regard. The hypothesis is put forward that inhibition of hypothalamic beta-endorphin release as probably resulting from the implantation of OB in the MPOA may be related to desensitization of the negative oestrogen feedback that is induced by similar preoptic oestrogen implantation.

Endometriosis-Associated Intestinal Tumours: A Consequence of Long-Term Unopposed Oestrogen?

A case of malignant transformation in an extra-ovarian site, 13 years after total abdominal hysterectomy and bilateral salpingo-oophorectomy, is discussed in a patient on long-term oestrogen implants, which highlights the potential risks surrounding the use of long-term oestrogen replacement therapy.

Prepubertal OVX increases IGF-I expression and bone accretion in C57BL/6J mice

It is generally well accepted that the pubertal surge in estrogen is responsible for the rapid bone accretion that occurs during puberty and that this effect is mediated by an estrogen-induced increase in growth hormone (GH)/insulin-like growth factor (IGF) action. To test the cause and effect relationship between estrogen and GH/IGF, we evaluated the consequence of ovariectomy (OVX) in prepubertal mice (C57BL/6J mice at 3 wk of age) on skeletal changes and the GH/IGF axis during puberty. Contrary to our expectations, OVX increased body weight (12-18%), bone mineral content (11%), bone length (4%), bone size (3%), and serum, liver, and bone IGF-I (30-50%) and decreased total body fat (18%) at 3 wk postsurgery. To determine whether estrogen is the key ovarian factor responsible for these changes, we performed a second experiment in which OVX mice were treated with placebo or estrogen implants. In addition to observing similar results compared with our first experiment, estrogen treatment partially rescued the increased body weight and bone size and completely rescued body fat and IGF-I levels. The increased bone accretion in OVX mice was due to increased bone formation rate (as determined by bone histomorphometry) and increased serum procollagen peptide. In conclusion, contrary to the known estrogen effect as an initiator of GH/IGF surge and thereby pubertal growth spurt, our findings demonstrate that loss of estrogen and/or other hormones during the prepubertal growth period effect leads to an increase in IGF-I production and bone accretion in mice.

Estrogen directly modulates circadian rhythms of PER2 expression in the uterus

Fluctuations in circulating estrogen and progesterone levels associated with the estrous cycle alter circadian rhythms of physiology and behavior in female rodents. Endogenously applied estrogen shortens the period of the locomotor activity rhythm in rodents. We recently found that estrogen implants affect Period (Per) gene expression in the suprachiasmatic nucleus (SCN; central clock) and uterus of rats in vivo. To explore whether estrogen directly influences the circadian clock in the SCN and/or tissues of the reproductive system, we examined the effects of 17beta-estradiol (E(2)) on PER2::LUCIFERASE (PER2::LUC) expression in tissue explant cultures from ovariectomized PER2::LUC knockin mice. E(2) applied to explanted cultures shortened the period of rhythmic PER2::LUC expression in the uterus but did not change the period of PER2::LUC expression in the SCN. Raloxifene, a selective estrogen receptor modulator and known E(2) antagonist in uterine tissues, attenuated the effect of E(2) on the period of the PER2::LUC rhythm in the uterus. These data indicate that estrogen directly affects the timing of the molecular clock in the uterus via an estrogen receptor-mediated response.

A Meta-Analysis Evaluation of Feeding Melengestrol Acetate to Feedlot Heifers Implanted with Estradiol, Trenbolone Acetate, or the Combination of Estradiol and Trenbolone Acetate

AbstractMixed models were used to study feeding melengestrol acetate (MGA) to feedlot heifers implanted with an estrogenic compound (EST), trenbolone acetate (TBA), or the combination of EST and TBA. One hundred one treatment means from 18 research trials were included in the analyses. Estrogenic implants increased DMI (p < 0.01) and LM area (P = 0.08). Estrogenic implant or MGA had no effect on percentage of carcasses grading low Choice or greater. Heifers implanted with TBA had greater (p < 0.05) final BW, ADG, hot carcass weight (HCW), and lower feed-togain ratio (FG) and YG. Trenbolone acetate tended to reduce the percentage YG 4 and 5 carcasses (P = 0.14) and percentage of carcasses grading low Choice or greater (P = 0.15). Interactions between MGA and EST were important (p < 0.01) for final BW, ADG, FG, and HCW, suggesting that the effect of MGA on these measurements depended upon EST implant. For heifers not implanted with EST, MGA improved (p < 0.01) FG and increased final BW, ADG, and HCW. For heifers implanted with EST, MGA had no effect on performance. Heifers fed MGA had greater (P = 0.05) DMI, increased (p < 0.01) fat depth, YG, and percentage YG 4 and 5 carcasses, and decreased (p < 0.01) LM area, regardless of implant status. In the absence of EST, MGA is effective in improving performance. However, when EST implants are used, there appears to be little performance benefit from feeding MGA.

SirT1 modulates the estrogen–insulin-like growth factor-1 signaling for postnatal development of mammary gland in mice

IntroductionEstrogen and insulin-like growth factor-1 (IGF-1) play important roles in mammary gland development and breast cancer. SirT1 is a highly conserved protein deacetylase that can regulate the insulin/IGF-1 signaling in lower organisms, as well as a growing number of transcription factors, including NF-κB, in mammalian cells. Whether SirT1 regulates the IGF-1 signaling for mammary gland development and function, however, is not clear. In the present study, this role of SirT1 was examined by studying SirT1-deficient mice.MethodsSirT1-deficient (SirT1ko/ko) mice were generated by crossing a new strain of mice harboring a conditional targeted mutation in the SirT1 gene (SirT1co/co) with CMV-Cre transgenic mice. Whole mount and histology analyses, immunofluorescence staining, immunohistochemistry, and western blotting were used to characterize mammary gland development in virgin and pregnant mice. The effect of exogenous estrogen was also examined by subcutaneous implantation of a slow-releasing pellet in the subscapular region.ResultsBoth male and female SirT1ko/ko mice can be fertile despite the growth retardation phenotype. Virgin SirT1ko/ko mice displayed impeded ductal morphogenesis, whereas pregnant SirT1ko/ko mice manifested lactation failure due to an underdeveloped lobuloalveolar network. Estrogen implantation was sufficient to rescue ductal morphogenesis. Exogenous estrogen reversed the increased basal level of IGF-1 binding protein-1 expression in SirT1ko/ko mammary tissues, but not that of IκBα expression, suggesting that increased levels of estrogen enhanced the production of local IGF-1 and rescued ductal morphogenesis. Additionally, TNFα treatment enhanced the level of the newly synthesized IκBα in SirT1ko/ko cells. SirT1 deficiency therefore affects the cellular response to multiple extrinsic signals.ConclusionSirT1 modulates the IGF-1 signaling critical for both growth regulation and mammary gland development in mice. SirT1 deficiency deregulates the expression of IGF-1 binding protein-1 and attenuates the effect of IGF-1 signals, including estrogen-stimulated local IGF-1 signaling for the onset of ductal morphogenesis. These findings suggest that the enzymatic activity of SirT1 may influence both normal growth and malignant growth of mammary epithelial cells.

Organic Approaches to the Treatment of Paraphilics and Sex Offenders

Emphasizing the power and fundamental nature—comparable to the basic mammalian drive for food—of sex drives and urges in almost everybody, including paraphilics and sex offenders, this article gives an overview of biologically-based, or “organic” approaches to the treatment of paraphilics and sex offenders. Organic treatment approaches for this population may be divided into surgical and pharmacotherapeutic categories. Surgical approaches include castration (orchiectomy), sterotactic (brain) surgery and estrogen implants, the latter two approaches are not used in the United States (U.S.). All surgical approaches act hormonally, in reducing or blocking the amount of circulating androgens in the subject. Pharmacotherapeutic approaches include: (1) Indirect-acting and direct-acting antiandrogen hormones, also intended to reduce or block the amount of circulating androgens in the subject. (2) Psychotropic medications for primary treatment of male aggressive hypersexuality, for treatment of co-occurring psychiatric symptomatology, or for both. (3) An experimental pharmacologic approach to the treatment of this population consists of the use of antiepileptic drugs, or “AED's” to stabilize the impulsivity/compulsivity of these subjects, in reducing the hypothesized “kindling” that may occur during impulsive/compulsive periods in these individuals. Whatever organic approach may be used for paraphilics and sex offenders, such an approach alone is not sufficient treatment for this population. Psychotherapeutic and cognitive/behavioral approaches must also be included in these individuals' treatment regimens. A companion piece to this article, giving an overview of psychotherapeutic and cognitive/behavioral treatment approaches to this population will be published in a future issue of this Journal.

A patient with confusing symptoms

A 48 year old woman presented to her general practitioner with a 16 month history of her mouth and fingers going numb and tingly. She also complained of feeling vacant and mentally detached. She reported numerous episodes of wandering, confusion, repeating words inappropriately, looking vacant, and not responding. All these events were witnessed by her children, but she had no recollection of them. All her symptoms were improved on eating. She was otherwise well, with no clinical features of Addison's disease, no past medical history of note, and was on no regular medication other than oestrogen implants. Home capillary glucose readings were 3.2 mmol/l, 2.7 mmol/l, 2.7 mmol/l, and 1.2 mmol/l (reference range 4-8 mmol/l). She was admitted for an overnight fast and was found to be completely unrousable by nursing staff in the morning. 1. What are the causes of hypoglycaemia? 2. What structure is seen on the computed tomography scan (line), and what is the abnormality (arrow)? 3. What does the histology image (figure 2) show? 4. What is the most likely diagnosis? 5. What is c peptide and what is its role in the diagnosis of hypoglycaemia? 1. A. Exogenous drugs—for example, insulin, oral hypoglycaemics, alcohol. B. Adrenal insufficiency or hypopituitarism. C. Liver failure. D. Islet cell tumour. E. Non-pancreatic neoplasm. F. Reactive …

A study of women on long-term hormone replacement therapy and their attitude to suggested cessation

Objective The study was undertaken to determine the effect of advice to discontinue hormone replacement therapy (HRT) on 100 women who were well established on treatment without side-effects.Method The study was retrospective from November 2003 to April 2004, in a single gynecological practice in London, UK. One hundred consecutive long-term estrogen and testosterone hormone implant users were assessed as to their knowledge of recent studies regarding risks of long-term HRT and whether they wished to discontinue hormones.Results All women receiving estrogen and testosterone implants, for a mean duration of 17.65 years (range 10–28 years), felt well informed concerning the Women's Health Initiative Study and the Million Women Study but only three women were happy to discontinue. The reasons given for the continuation of therapy were that they felt well and their quality of life had greatly improved. The mean estradiol and testosterone levels were 921 pmol/l and 1.91 nmol/l, respectively.Conclusions The high rate of continuation of hormone treatment indicates that, despite the recent adverse publicity, these women feel well informed and were not willing to discontinue with their hormone therapy if they felt well. A regular discussion of the risks and benefits of HRT remains mandatory.

Effects of Combined Estrogen and Progesterone on Brain Infarction in Reproductively Senescent Female Rats

Recent data from the Women's Health Initiative have highlighted many fundamental issues about the utility and safety of long-term estrogen use in women. Current hormone replacement therapy for postmenopausal women incorporates progestin with estrogen, but it is uncertain if combined therapy provides major cerebrovascular risks or benefits to these women. No experimental animal stroke studies have examined combined hormone administration. The authors tested the hypothesis that combined hormone treatment reduces ischemic injury in middle-aged female rat brain. Reproductively senescent female rats underwent 2-hour middle cerebral artery occlusion (MCAO) followed by 22 hours reperfusion. Estrogen implants were placed subcutaneously at least 7 days before MCAO, and progesterone intraperitoneal injections were given 30 minutes before MCAO, at initiation, and at 6 hours of reperfusion. Rats received no hormone, a 25-microg estrogen implant, a 25-microg estrogen implant plus 5 mg/kg intraperitoneal progesterone, or 5 mg/kg intraperitoneal progesterone. Cortical, caudoputamen, and total infarct volumes were assessed by 2,3,5-triphenyltetrazolium chloride staining and digital image analysis at 22 hours reperfusion. Cortical and total infarct volumes, except in the acute progesterone-treated group, were significantly attenuated in all estrogen-alone and combined hormone-treated groups. There were no significant differences in caudoputamen infarct volumes in all hormone-treated groups as compared with untreated rats. These data have potential clinical implications relative to stroke for postmenopausal women taking combined hormone replacement therapy.

Effects of estrogen on messenger ribonucleic acid expression patterns of extracellular matrix proteases in the primate colon.

Recent studies suggest that hormone replacement therapy in postmenopausal women can decrease colon cancer risk. To better understand the molecular effects of estrogen on the colon, we examined the effects of estrogen replacement on gene expression of proteases associated with extracellular matrix degradation in rhesus monkey colon tissue. Rhesus monkeys were oophorectomized and one-half were implanted with estradiol capsules. After five months, colon tissue was harvested, and messenger ribonucleic acid was extracted and converted to cDNA. The cDNA was hybridized with a DNA array spotted with cDNA corresponding to genes involved in extracellular matrix remodeling. Selected genes exhibiting significant differential expression were validated using reverse transcriptase-polymerase chain reaction and real-time polymerase chain reaction analysis. Of 96 genes assessed, nearly 18 percent showed a twofold or greater change in expression; however, signals from approximately 65 percent of genes assayed were below detection levels. A distinct pattern of decreased gene expression was observed in colon tissue of animals with estrogen implants compared with females without estrogen replacement. Reverse transcriptase-polymerase chain reaction confirmed decreased expression in estrogen-replaced vs. hormone-deprived tissues of proteases cathepsin-D and caspase-8. Real-time polymerase chain reaction data confirmed the suppression of proteases A disintegrin and mettaloproteinase with thrombospondin motifs, type 1 and matrix metalloproteinase-2 with estrogen replacement in colon tissue. This is the first investigation of the specific effects of estrogen in normal primate colon. Estrogen replacement suppressed expression of several proteases linked to tumor growth and metastasis. This study provides the groundwork for targeted future studies to further characterize the role of estrogen in colon tissue.

Estrogen decreases zinc transporter 3 expression and synaptic vesicle zinc levels in mouse brain.

Previous studies suggest that female sex hormones modulate synaptic zinc levels, which may influence amyloid plaque formation and Alzheimer's disease progression. We examined the effects of ovariectomy and estrogen supplement on the levels of synaptic zinc and zinc transporter protein Znt3 in the brain. Ovariectomy was performed on 5-month-old mice, and 2 weeks later, pellets containing vehicle, low (0.18 mg/pellet), or high dose (0.72 mg) 17beta-estradiol were implanted. After 4 weeks, animals were decapitated, and blood and brain were collected for analysis. Blood analysis indicated that estrogen implants altered plasma estrogen levels in a dose-dependent manner. Analysis of brain tissue showed that ovariectomy raised hippocampal synaptic vesicle zinc levels, whereas estrogen replacement lowered these zinc levels. Western blots revealed that Znt3 levels in the brain were modulated in parallel with synaptic zinc levels, whereas no change was detected in the levels of Znt3 mRNA, as determined by Northern blot and reverse transcriptase-PCR analysis. However, mRNA levels of the delta subunit of adaptor protein complex (AP)-3, which modulates the level of Znt3 levels, were altered by estrogen depletion or replacement. These data demonstrate that estrogen alters the levels of Znt3 and synaptic vesicle zinc in female mice, probably through changing AP-3 delta expression. Since synaptic zinc may play a key role in neuronal death in acute brain injury as well as in plaque formation in Alzheimer's disease, and since estrogen may be beneficial in both conditions, our results may provide new insights into the effects of estrogen on the brain.

Sexual dimorphism in the contribution of protein kinase c isoforms to nociception in the streptozotocin diabetic rat

The contribution of second messenger signaling, glucose level and sex hormones to sexual dimorphism in the streptozotocin model of diabetic painful peripheral neuropathy was evaluated. Streptozotocin induced elevation of blood glucose and mechanical hyperalgesia (measured by the Randall-Selitto paw-withdrawal test) were both greater in female rats. Ovariectomy abolished and estrogen implants reconstituted this sexual dimorphism; gonadectomy in males had no effect. An inhibitor of protein kinase Cϵ attenuated hyperalgesia in males and ovariectomized females, but not in normal females or in ovariectomized females with estrogen implants, whereas inhibitors of protein kinase Cδ attenuated hyperalgesia in females but not in males. Inhibitors of protein kinase A, protein kinase C (non-selective), protein kinase G and nitric oxide synthase attenuated hyperalgesia equally in both sexes. Higher blood glucose levels in diabetic females were also sex hormone dependent, and magnitude of hyperalgesia correlated with blood glucose level in diabetic male and female rats. These results demonstrate sexual dimorphism in diabetic hyperalgesia, mediated by sex hormone dependent differences in protein kinase Cϵ and protein kinase Cδ signaling and blood glucose levels and suggest that sex may be an important factor to be considered in the treatment of symptomatic diabetic neuropathy.

Hyperalgesic priming in the rat demonstrates marked sexual dimorphism

In male rats, carrageenan (CAR)-induced inflammation or exposure to a selective protein kinase C epsilon (PKCε) agonist (ψεRACK) produces prolongation of the hyperalgesia induced by a subsequent exposure to an inflammatory mediator, a phenomenon referred to as hyperalgesic priming. Since many chronic inflammatory conditions are sexually dimorphic, we tested the hypothesis that hyperalgesic priming is sexually dimorphic. Prior injection of CAR or ψεRACK produced a prolongation of the hyperalgesia induced by a subsequent injection of prostaglandin E 2, from less than 3 h to greater than 24 h, but only in male rats. In ovariectomized female rats priming with CAR and ψεRACK produced hyperalgesic priming effects similar to that observed in the male rat, and this effect was reversed by estrogen replacement. While gonadectomy in males had no effect on CAR and ψεRACK induced hyperalgesic priming, female phenotype was observed following implantation of estrogen in males. Thus, mechanisms mediating the development of hyperalgesic priming produced by inflammation are suppressed by estrogen. This regulation of priming by estrogen appears to occur at or downstream of the activation of PKCε.

Exposure of neonatal female rats to p-tert-octylphenol disrupts afternoon surges of luteinizing hormone, follicle-stimulating hormone and prolactin secretion, and interferes with sexual receptive behavior in adulthood.

The present study investigated the effects of exposure of neonatal female rats to p-tert-octylphenol (OP) on estrogen-induced afternoon surges of LH, FSH, and prolactin (PRL) secretion, and on sexual behavior in adulthood. After birth, one group of female Wistar rat pups received s.c. injections of OP (100 mg/kg body weight [BW]; OP group) dissolved in DMSO, while the control group received DMSO only (DMSO group). In order to make a qualitative comparison, a third group was injected with estradiol-17beta (500 microg/kg BW; estradiol group) dissolved in DMSO. Injections were given on Days 1, 3, 5, 7, 9, 11, 13, and 15 of age. The rats from the OP and estradiol groups that were used for subsequent experiments were in persistent vaginal estrus. Spontaneous LH surge measured at Postnatal Days (PND) 78-81 was observed only in the DMSO group on the afternoon of the day of proestrus. At PND 115, randomly selected rats from each of three treatment groups were bilaterally ovariectomized (ovx), and 8 days later, Silastic capsules containing estradiol-17beta were implanted under the skin. Estrogen implants stimulated afternoon surges of LH, FSH, and PRL for two consecutive days in the DMSO group, but not in the OP and estradiol groups. Rats from the OP and DMSO groups underwent ovx at PND 186, and 6 days later they were treated with a combination of estradiol benzoate s.c. (15 microg/kg BW) and progesterone s.c. (2 mg/kg BW) to test the lordosis reflex. In response to this hormone treatment and mounting stimulus delivered by the stud male rats, the OP-treated rats were less receptive compared with control DMSO-treated rats, and thus the lordosis quotient and lordosis rating were significantly (P < 0.05) reduced in the OP group compared with the DMSO group. Analysis of the area of the sexually dimorphic nucleus of the preoptic area of the brain revealed that the area of this nucleus was larger in the OP group than it was in control DMSO rats. We conclude that the exposure of neonatal female rats to higher doses of OP disrupts the cyclic release of LH, FSH, and PRL, and interferes with the display of sexual receptive behavior in adulthood.

Weight Gain in Suckling Calves Following Revalor-G®, Ralgro™, or Synovex®-C

This study is the first report designed to compare approved estrogenic implants Ralgro™ and Synovex®-C with Revalor-G® in suckling calves. An on-farm comparison of the BW gain response following implantation was conducted using 156 native, commercial crossbred suckling steers (with similar genetics) on typical Mississippi fescue-based cow/calf operations. Calves were weighed (avg. 133.0 kg), randomized, and allocated to one of the three treatments. The calves which ranged from 2 to 4 mo of age were returned to their dams following routine processing and weighed again (236.2 kg) at 111 d (overall BW gain was 103.3 kg). Least square means for Revalor-G and Ralgro were not significantly different for BW gain and ADG (105.8/0.96 and 104.7/0.95, respectively). However, both Revalor-G and Ralgro significantly improved BW gain total and rate over Synovex-C. Although not currently approved for use in suckling calves, Revalor-G was comparable to Ralgro as a suckling-calf growth modifier.

Morphologic and molecular analysis of estrogen-induced pituitary tumorigenesis in targeted disruption of transforming growth factor-beta receptor type II and/or p27 mice.

The critical genes and products involved in estrogen-induced tumorigenesis of the pituitary gland were investigated in heterozygous transforming growth factor-beta (TGF-beta) receptor type II and p27 knockout mouse models. Tgfbr2(+/-), p27(+/-); Tgfbr2(+/-), and p27(+/-) mice and C57BL/6J wild-type mice received sc implantation of estrogen or placebo pellets for 16 or 25 wk, after which the mice were sacrificed and their pituitary glands removed for examination. The bromodeoxyuridine labeling indexes in tissue from both the anterior and intermediate pituitary lobes from p27 (+/-) and Tgfbr2(+/-); p27(+/-) mice were significantly higher than those from wild-type and Tgfbr2(+/-) mice after treatment with estrogen for 16 wk. Pituitary tumorigenesis was significantly accelerated in Tgfbr2(+/-), p27(+/-), and Tgfbr2(+/-); p27(+/-) mice compared with wild-type mice after treatment with estrogen for 16 wk. Pituitary tumorigenesis was not accelerated in Tgfbr2(+/-); p27(+/-) mice compared with Tgfbr2(+/-) or p27(+/-) mice. Expression of TGF-beta receptor type II mRNA was lower in the pituitary gland of Tgfbr2(+/-) mice than in wild-type mice before estrogen treatment and was significantly reduced after treatment. Pituitary tumorigenesis is accelerated in mice with severe TGF-beta resistance, and greatly accelerated in mice with TGF-beta resistance combined with decreased p27 expression compared with wild-type mice. Both the TGF-beta receptor type II gene and p27 gene and their products are involved in estrogen-induced tumorigenesis.

Upregulation of pancreatic polypeptide-sensitive neuropeptide Y (NPY) receptors in estrogen-induced hypertrophy of the anterior pituitary gland in the Fischer-344 rat

Implants of diethylstilbestrol inducing anterior pituitary prolactinomas in female Fischer-344 rats produced a considerable elevation of high-affinity binding of either rat or human pancreatic polypeptide (hPP). No comparable upregulation of high-affinity binding sites was noted for the ligand [ 125I](Leu 31,Pro 34)hPYY (LP-PYY) (masked by 2 nM hPP to force selectivity for the Y 1 sites), or of the Y 2-selective ligand [ 125I]hPYY(3–36). The Y 5-like sites displayed the rank order of potency of hPP=rPP, hNPY, LP-PYY>pPYY(1–36)>hNPY(2–36)>hPYY(3–36)≫aPP, similar to the previously described rabbit kidney or hypothalamic Y 5-like receptors. The PP binding in the anterior pituitary was not sensitive to the Y 1-selective non-peptidic antagonist BIBP-3226. The PP binding was highly sensitive to alkali metal cations, and to a N5-substituted amiloride antagonist of sodium transport, but not to a C2-guanido substituted amiloride antagonist of sodium channels. The binding was also sensitive to phospholipase C antagonist U-73122, and to alkylating α-adrenergic agonist chloroethylclonidine. Lactotrophs isolated in Percoll gradients after enzymic dispersion of the anterior pituitary gland retained the high-affinity PP binding. Following removal of estrogen implants, the hPP binding sites decreased to very low levels within 3 days, in parallel to the decrease of plasma prolactin.

Hormone replacement therapy and breast cancer.

The concern that postmenopausal hormone replacement therapy (HRT) may cause cancer of the breast has lead to an enormous volume of research in epidemiology, endocrinology and tumour cell biology. The epidemiology has become extremely sophisticated because the anticipated effect is small and there are several confounding factors. The consensus today is that long-term HRT (>10 years) is associated with an increase in the risk of breast cancer which, on average, is equivalent to delaying menopause for the same period of time that the patient is on treatment. The risk is related to endogenous and exogenous oestrogen levels. Studies that have investigated individual susceptibility are reviewed, as are environmental factors such as the interaction of HRT with alcohol intake. The clinical implication of these data is that the dosage of HRT should be the smallest that is efficacious. Subcutaneous implants of oestrogen typically cause very high oestrogen levels and, in the opinion of this reviewer, should be restricted to women unable to take or absorb oestrogen by mouth or percutaneously. Finally, the issue of HRT for women with a history of breast cancer is considered. The potential is discussed for treatment of women with severe symptoms of oestrogen deficiency with a low dose of oestrogen, together with a selective oestrogen receptor modulator to protect the breast.

Placebos and placebo effects in medicine: historical overview.

some experimental intervention. Although the most frequently used placebo is the 'sugar pill' in drug trials, placebos can be and have been used for all kinds of interventions, ranging from placebo ultrasound in the treatment of pressure ulcers and placebo surgery in the treatment of osteoarthritis to sham traction in the treatment of low back pain and placebo oestrogen implants in the prevention of menopause symptoms.