Estradiol Implants Research Articles

Tamoxifen induces regression of estradiol-induced mammary cancer in the ACI.COP-Ept2 rat model

The ACI rat is a unique model of human breast cancer in that mammary cancers are induced by estrogen without carcinogens, irradiation, xenografts or transgenic manipulations. We sought to characterize mammary cancers in a congenic variant of the ACI rat, the ACI.COP-Ept2. All rats with estradiol implants developed mammary cancers in 5-7 months. Rats bearing estradiol-induced mammary cancers were treated with tamoxifen for three weeks. Tamoxifen reduced tumor mass, measured by magnetic resonance imaging, by 89%. Tumors expressed estrogen receptors (ER), progesterone receptor (PR), and Erbb2. ERalpha and PR were overexpressed in tumor compared to adjacent non-tumor mammary gland. Thus, this model is highly relevant to hormone responsive human breast cancers.

“Reprint of” Testosterone enhances estradiol’s effects on postmenopausal bone density and sexuality

To investigate the role of androgens in increasing bone density and improving low libido in postmenopausal women, we have studied the long-term effects of estradiol and testosterone implants on bone mineral density and sexuality in a prospective, 2 year, single-blind randomised trial. Thirty-four postmenopausal volunteers were randomised to treatment with either estradiol implants 50 mg alone (E) or estradiol 50 mg plus testosterone 50 mg (E&T), administered 3-monthly for 2 years. Cyclical oral progestins were taken by those women with an intact uterus. Thirty-two women completed the study. BMD (DEXA) of total body, lumbar vertebrae (L1–L4) and hip area increased significantly in both treatment groups. BMD increased more rapidly in the testosterone treated group at all sites. A substantially greater increase in BMD occurred in the E&T group for total body ( P < 0.008), vertebral L1–L4 ( P < 0.001) and trochanteric ( P < 0.005) measurements. All sexual parameters (Sabbatsberg sexual self-rating scale) improved significantly in both groups. Addition of testosterone resulted in a significantly greater improvement compared to E for sexual activity (P < 0.03), satisfaction ( P < 0.03), pleasure ( P < 0.01), orgasm ( P < 0.035) and relevancy ( P < 0.05). Total cholesterol and LDL-cholesterol fell in both groups as did total body fat. Total body fat-free mass (DEXA, anthropometry, impedance) increased in the E&T group only. We concluded that in postmenopausal women, treatment with combined estradiol and testosterone implants was more effective in increasing bone mineral density in the hip and lumbar spine than estradiol implants alone. Significantly greater improvement in sexuality was observed with combined therapy, verifying the therapeutic value of testosterone implants for diminished libido in postmenopausal women. The favourable estrogenic effects on lipids were preserved in women treated with T, in association with beneficial changes in body composition.

Effect of forebrain implants of testosterone or estradiol on scent-marking and sexual behavior in male and female rabbits

Chinning consists of rubbing the chin against an object, thereby depositing secretions from the submandibular glands. As mating, chinning is stimulated in male and female rabbits by testosterone and estradiol, respectively. To investigate the brain sites where steroids act to stimulate chinning and mating we implanted into the ventromedial hypothalamus (VMH) or the medial preoptic area (MPOA) of gonadectomized male and female rabbits testosterone propionate (TP; males) or estradiol benzoate (EB; females) and quantified chinning and sexual behavior. EB implants into the VMH or MPOA reliably stimulated chinning in females. Most of those implanted into the VMH and around half of the ones receiving EB into MPOA or diagonal band of Broca (DBB) showed lordosis. Chinning, but not sexual behavior, was stimulated in males by TP implants into the MPOA or DBB. Neither chinning nor mounting were reliably displayed by males following TP implants into the VMH. Results indicate that, in females, the VMH is an estrogen-sensitive brain area that stimulates both chinning and lordosis while the MPOA seems to contain subpopulations of neurons involved in either behavior. In males, androgen-sensitive neurons of the MPOA, but not the VMH, are involved in chinning stimulation but it is unclear if these areas also participate in the regulation of copulatory behavior.

Histopathological evidence for an association of inflammation with ductal pin‐like lesions but not with ductal adenocarcinoma in the prostate of the noble rat

Chronic inflammation may contribute to the development of prostate cancer. The goal of this study was to determine the possible association of prostatic inflammation, prostatic intraepithelial neoplasia (PIN)-like lesion, and prostate cancer, and to assess the androgen and estrogen dependency of the early steps of carcinogenesis. Noble rats were treated with testosterone and estradiol implants for 13, 18, or 26 weeks. Hormone dependency of the lesions was studied in a subset of animals by removing hormone implants for 3 weeks after 15 weeks treatment time. After treatment for 13 weeks, acute and chronic inflammation was found in the dorsolateral prostate lobes and both inflammation and PIN-like lesions were present in the periurethal area of the prostate in all animals (n = 8). Following hormone exposure for 18 and 26 weeks, inflammation in the prostate remained, and adenocarcinomas in the periurethal prostate area with no adjacent inflammation were observed in all 18 animals studied. When both hormone implants were removed after 15 weeks, PIN-like lesions progressed further to adenocarcinoma only in two of seven animals. When only the estradiol implants were removed, three of five animals developed adenocarcinomas. Even though adenocarcinomas were not morphologically associated with inflammation, PIN-like lesions preceding adenocarcinoma were found in close association with inflammation, pointing towards a possible initiator role of inflammation in the early steps of prostatic carcinogenesis. Further, these results indicate that both androgens and estrogens together play a significant role in the induction of inflammation and prostatic cancer in this model.

Dynamics of estrogen-induced oxidative stress.

The objective of this study was to assess the dynamics of oxidative damage to cellular macromolecules such as proteins, lipids and DNA under conditions of oxidative stress triggering early stages of estrogen-dependent carcinogenesis. A rodent model of carcinogenesis was used. Syrian hamsters were sacrificed after 1, 3, 5 h and one month from the initial implantation of estradiol. Matching control groups were used. Kidneys as target organs for estradiol-mediated oxidative stress were excised and homogenized for biochemical assays. Subcellular fractions were isolated. Carbonyl groups (as a marker of protein oxidation) and lipid hydroxyperoxides were assessed. DNA was isolated and 8-oxodGuo was assessed. Electron paramagnetic resonance spectroscopy was used to confirm the results for lipid peroxidation. Exposition to estradiol in the rodent model leads to damage of macromolecules of the cell, including proteins and DNA, but not lipids. Proteins appear to be the primary target of the damage but are closely followed by DNA. It has previously been speculated that protein peroxides can increase DNA modifications. This time sequence was observed in our study. Nevertheless, the direct relation between protein and DNA damage still remains unsolved.

Androgen receptor is essential for sexual differentiation of responses to olfactory cues in mice

During sexual differentiation males and females are exposed to different levels of testosterone, which promotes sex differences in the adult brain and in behavior. Testosterone can act after aromatization or reduction via a number of steroid hormone receptors. Here we provide new evidence that the androgen receptor (AR) is essential for sexual differentiation in mice. We used mice carrying the testicular feminization (Tfm) mutation of the AR. Adult Tfm males, wild-type male and female littermates were gonadectomized and given subcutaneous estradiol implants. In all sexually dimorphic traits, Tfm males had responses equivalent to females and different from males. In simultaneous choice tests, males spent significantly more time investigating female-soiled bedding, whereas females and Tfm males preferred to investigate male-soiled bedding. Tfm males and females did not have a partner preference in tests with awake stimulus animals, whereas males showed a preference for females over males. Exposure to male-soiled, but not clean, bedding produced a significant increase in c-Fos-immunoreactive cells in the medial preoptic area and bed nucleus of the stria terminalis in Tfm males and females, no increase was noted in males. Masculine sexual behavior (mounting and thrusting) was not sexually dimorphic, and all groups displayed these behaviors. Our results support data collected in humans suggesting a role for the androgen receptor in sexual differentiation of social preferences and neural responses to pheromones.

Estradiol decreases anxiety behavior and enhances inhibitory avoidance and gestational stress produces opposite effects

Although there is evidence that estradiol has effects in women and in animal models to reduce anxiety and depressive behavior and enhance performance in some cognitive tasks, this is not seen among all individuals. Given the interaction between estradiol and hypothalamic–pituitary–adrenal function, we hypothesized that an individual's prior exposure to stress may mitigate some of the subsequent effects of estradiol. To address this, rats were exposed to gestational stress, or not, to determine if stress exposure during development alters behavioral responses to estradiol in adulthood. If estradiol's effects on anxiety and cognitive behavior are modulated by prior stress experience, then gestationally-stressed rats administered estradiol should have decreased anti-anxiety (open field, elevated plus maze) behavior and cognitive performance in the inhibitory avoidance task. Offspring of dams that were exposed to restraint stress daily on gestational days 14–20, or no such manipulation, were used as adults either intact in behavioral estrus (high estradiol) or diestrus (low estradiol), or ovariectomized (OVX) with empty or estradiol-containing silastic implants. Rats were used for blood collection to determine plasma corticosterone and estradiol concentrations, or were used for behavioral testing. Compared with rats in diestrus or OVX and vehicle-replaced, rats in behavioral estrus and OVX rats with estradiol implants had higher estradiol concentrations, entered more central squares in an open field, spent more time on the open arms of the plus maze, and had a longer latency to crossover to the dark, shock-associated side of the inhibitory avoidance chamber. Gestational stress increased plasma corticosterone but not estradiol levels, decreased plus maze open arm time in cycling rats, and decreased inhibitory avoidance performance. Thus, estradiol and gestational stress can have opposite effects on anxiety and inhibitory avoidance performance.

Effects of subdermal implants of estradiol and testosterone on the endometrium of postmenopausal women

A retrospective review of the medical records of 258 postmenopausal patients using estradiol and testosterone implants as combined hormone therapy was carried out to evaluate the effects of testosterone on the endometrium after two years of continuous use. Endometrial thickness was measured by ultrasonography. Histology was performed on samples of thickened endometria obtained during hysteroscopy with biopsy. In the 44 patients in whom endometrial thickening was >5 mm at the end of the second year of implant use, the most frequent finding at hysteroscopy was polypoid lesion in 61.3% of cases, followed by normal uterine cavity in 31.8% of cases and submucous myoma in 6.8%. Histology of the endometrial samples confirmed endometrial polyp in 38.6% of cases, a histologically normal endometrium in 31.8% of cases, simple endometrial hyperplasia in 20.4% of cases, and myoma and atrophic endometrium in 4.5%. It is possible that testosterone may exert its antiproliferative effects on the endometrium but not on polyps in an action similar to that exerted by combined estrogen/progestin therapies. A greater incidence of simple, low-grade endometrial hyperplasia was found in our study compared with studies using continuous estrogen/progestin regimens. The use of progestins as the ideal endometrial protection should therefore be reconsidered.

Gender-dependent modulation of brain monoamines and anxiety-like behaviors in mice with genetic serotonin transporter and BDNF deficiencies.

1. Brain-derived neurotrophic factor (BDNF) supports serotonergic neuronal development and our recent study found that heterozygous mice lacking one BDNF gene allele interbred with male serotonin transporter (SERT) knockout mice had greater reductions in brain tissue serotonin concentrations, greater increases in anxiety-like behaviors and greater ACTH responses to stress than found in the SERT knockout mice alone. 2. We investigated here whether there might be gender differences in these consequences of combined SERT and BDNF deficiencies by extending the original studies to female mice, and also to an examination of the effects of ovariectomy and tamoxifen in these female mice, and of 21-day 17-beta estradiol implantation to male mice. 3. We found that unlike the male SERTxBDNF-deficient mice, female SERTxBDNF mice appeared protected by their gender in having significantly lesser reductions in serotonin concentrations in hypothalamus and other brain regions than males, relative to controls. Likewise, in the elevated plus maze, female SERTxBDNF-deficient mice demonstrated no increases in the anxiety-like behaviors previously found in males. 4. Furthermore, female SERTxBDNF mice did not manifest the approximately 40% reduction in the expression of TrkB receptors or the approximately 30% reductions in dopamine and its metabolites that male SERTxBDNF did. After estradiol implantation in male SERTxBDNF mice, hypothalamic serotonin was significantly increased compared to vehicle-implanted mice. These findings support the hypothesis that estrogen may enhance BDNF function via its TrkB receptor, leading to alterations in the serotonin circuits, which modulate anxiety-like behaviors. 5. This double-mutant mouse model contributes to the knowledge base that will help in understanding genexgenexgender interactions in studies of SERT and BDNF gene polymorphisms in human genetic diseases such as anxiety disorders and depression.

A complex containing α6β1-integrin and phosphorylated focal adhesion kinase between Sertoli cells and elongated spermatids during spermatid release from the seminiferous epithelium

Spermiation is the final step of spermatogenesis and culminates in the disengagement (release) of elongated spermatids from Sertoli cells into the seminiferous tubule lumen. Spermiation failure, wherein spermatids are retained by Sertoli cells instead of releasing, occurs after hormone suppression. The mechanisms involved in spermatid disengagement and retention are not well understood. We previously showed that beta(1)-integrin is associated with spermatids until the point of disengagement, but the ectoplasmic specialisation junction (ES) is not. The aims of this paper are to further characterise the complex that is present immediately prior to spermatid disengagement by identifying the alpha-integrin form dimerised with beta(1)-integrin, localising focal adhesion kinase (FAK) and determining if microtubules are involved. Adult Sprague-Dawley rats received testosterone and oestradiol implants and an FSH antibody for 7 days to suppress testicular testosterone and FSH and induce spermiation failure. Control rats were treated with saline. Immunohistochemical analysis showed that alpha(6)-integrin and a phosphorylated form of FAK (FAK-Tyr(397)) are present between late spermatids and Sertoli cells after ES removal, until the point of disengagement, and both proteins remain associated with retained spermatids after spermiation failure induced by hormone suppression. Using dual-label immunofluorescence, tubulins (and thus microtubules) were observed to co-localise with ES, but were neither associated with elongated spermatids just prior to release nor with retained spermatids following hormone suppression. These results suggest that microtubules are not involved in the final release of spermatids from Sertoli cells. We conclude that spermatid release during spermiation is mediated by a 'disengagement complex' containing alpha(6)beta(1)-integrin and phospho-FAK, the function of which can be affected by gonadotrophin suppression.

Comparison of alternative beef production systems based on forage finishing or grain-forage diets with or without growth promotants: 1. Feedlot performance, carcass quality, and production costs

Forty Angus-cross steers were used to evaluate 5 beef cattle management regimens for their effect on growth performance, carcass characteristics, and cost of production. A 98-d growing phase was incorporated using grass silage with or without growth promotants (trenbolone acetate + estradiol implants, and monensin in the feed) or soybean meal. Dietary treatments in the finishing phase were developed, with or without addition of the same growth promotants, based on exclusive feeding of forages with minimal supplementation or the feeding of barley-based diets. Overall, ADG for animals treated with growth promotants or fed supplemented diets (soybean meal and barley) was increased (P < 0.01) by 25 and 21%, respectively, compared with steers reared on grass silage alone and not treated with growth promotants. Except for HCW (P < 0.01), the use of growth promotants did not affect carcass measurements. Increasing the proportion of barley in the diet of steers finished on forage produced a heavier HCW (P < 0.01) and a greater (P < 0.01) quality grade. Because of their lower HCW and quality grade, cattle targeted to a forage-fed, nonimplanted beef market would need to garner a 16% premium to be economically competitive with cattle finished conventionally.

Suppression of Follicle Wave Emergence in Cyclic Ewes by Supraphysiologic Concentrations of Estradiol-17beta and Induction with a Physiologic Dose of Exogenous Ovine Follicle-Stimulating Hormone1

Follicle waves are preceded by follicle-stimulating hormone (FSH) peaks in ewes. The purpose of the present study was to see whether estradiol implant treatment would block FSH peaks to create a model in which the effect of the timing and mode of FSH peaks could be studied by ovine FSH (oFSH) injection. In Experiment 1, 10 ewes received estradiol-17beta implants on Day 4 after ovulation (Day 0, day of ovulation); five ewes received large implants, and five ewes received small implants. Five control ewes received empty implants. In Experiment 2, 12 ewes received large implants on Day 4. On Day 9, six ewes received oFSH twice, 8 h apart (0.5 microg/kg; s.c.). Implants were left in place for 10 days in both experiments. In both studies, ovarian ultrasonography and blood sampling was done daily. In Experiment 1, estradiol concentrations were significantly higher in ewes with large implants (10.4 +/- 0.7 pg/ml) compared with controls (3.9 +/- 0.7 pg/ml) and ewes with small implants (5.4 +/- 0.7 pg/ml; P < 0.001). A significant reduction was found in mean FSH peak concentration (31%; P < 0.05) and FSH peak amplitude (45%; P < 0.05) in ewes with large implants compared with controls. Mean and basal FSH concentrations were unaffected by the large implants. The large implants halted follicle-wave emergence between Day 0 and 8 after implant insertion. The small follicle pool (2-3 mm in diameter) was unaffected by the large implants. When oFSH was injected into ewes with large implants, a follicle wave emerged 1.5 +/- 0.5 days after injection; however, in ewes given saline alone, a follicle wave emerged 4.8 +/- 0.8 days after injection (P < 0.01). We concluded that truncation of FSH peaks by estradiol implants prevented follicle-wave emergence, but injection of physiologic concentrations of oFSH reinitiated follicle-wave emergence.

Estrogenic support of motoneuron dendritic growth via the neuromuscular periphery in a sexually dimorphic motor system

The lumbar spinal cord of rats contains the sexually dimorphic, steroid-sensitive spinal nucleus of the bulbocavernosus (SNB). In males, the growth of SNB dendrites is steroid-dependent: dendrites fail to grow after castration, but grow in castrates treated with androgens or estrogens. Blocking estradiol synthesis or estrogen receptors in gonadally intact males attenuates SNB dendritic growth, suggesting that estrogens are required and must be able to act at their receptors to support normal masculine dendritic growth. However, SNB motoneurons do not accumulate estrogens, suggesting that estrogens act indirectly to support SNB dendritic growth. In this experiment, we examined whether local estrogen action in the neuromuscular periphery was involved in the postnatal development of SNB motoneurons. Motoneuron morphology was assessed in gonadally intact and castrated males. Gonadally intact males were left untreated or given either blank or tamoxifen implants sutured to the target musculature, or tamoxifen interscapular implants. Castrated males were left untreated or were given estradiol by muscle or interscapular implants or systemic injection during the period of SNB dendritic growth. At postnatal day 28, when SNB dendritic length is normally maximal, SNB motoneurons were retrogradely labeled with cholera toxin-HRP and reconstructed in three dimensions. While interscapular tamoxifen implants were ineffective, blocking estrogen receptors at the target musculature resulted in attenuation of SNB dendritic growth. In contrast, while interscapular implants of estradiol were ineffective, local treatment with estradiol at the target musculature in castrated males resulted in masculinization of dendritic growth. Thus, estrogens may act by an indirect action in the neuromuscular periphery to support SNB dendritic growth.

Moderate dosage estrogen–androgen therapy improves continuation rates in postmenopausal women: impact of the WHI reports

Objective The purpose of this report is not to provide descriptive data for practice recommendations but to point the way to more liberal thinking than the conservatism of today. The patients in this historical practice, where moderate dosages of estrogen are used, with androgens added when indicated, continue hormone replacement therapy (HRT) for many years. These women were audited to determine the reasons for continuance.Design During the 3 years from 1996 to 1999, 814 women have been followed prospectively, the date of this first visit recorded, as well as the date last seen, the years of hormone use, and their current hormone replacement, so that continuation rates could be determined. The records of the patients were reviewed in January 2005 to determine the impact of the Women's Health Initiative (WHI).Results Of the 814 patients, there were 573 surgically menopausal women with a mean age of 61.8±3.25 years and 241 naturally menopausal women with a mean age of 58.6±3.08 years. During the 3 years of observation, 692 women continued HRT while 122 discontinued their therapy. Of those continuing therapy, 606 were treated with the implantation of various combinations of estradiol and testosterone pellets, while 86 used injectables, patches or oral hormones. Continuation rates for pellet patients were 96.7% for 10 years, 88.8% for 20 years, and 21.9% for 40 or more years. Continuation rates for the other hormone users were 53.5% for 10 years and 20.9% for 20 years. Eighty-one percent of the patients were prescribed progestogens, and 18 different progestogens or dosages or regimens were used to individualize therapy and provide as side-effect-free a regimen as possible. Continuation rates in the 692 remaining patients declined to 66.7% during the next 5 years.Conclusions Moderate dosages of estrogens, with androgens added when indicated, improve continuation rates. Therapy must be individualized so that not only are menopausal symptoms relieved but also side-effects are minimal and women continue to feel good. The implantation of estradiol and testosterone pellets is not necessary for even the majority of postmenopausal women. However, estrogen dosages must be adequate to provide a sense of well-being. After the WHI reports, continuation rates declined more rapidly.

Regulation of FoxO1 Transcription Factor by Nitric Oxide and Cyclic GMP in Cultured Rat Granulosa Cells

FoxO1 is a transcription factor implicated in a multitude of physiological processes including cell cycle progression, apoptosis and insulin signaling. Recent findings indicate that FoxO1 is a key regulator during the proliferation and maturation of granulosa cells. Over the past several years, it has become evident that nitric oxide (NO) and cGMP modulate ovarian function. There has been no information, however, about whether NO-cGMP affects FoxO1 expression or about the relationship between NO-cGMP and FoxO1. In the present study, we used immunoblot analysis to determine whether NO and cGMP affect FoxO1 expression in cultured granulosa cells. Our results clearly showed that FSH suppressed FoxO1 expression in a time-dependent manner, and that NO-cGMP stimulated FoxO1 expression in cultured granulosa cells. In addition, this stimulatory effects of NO and cGMP can be blocked by FSH in cultured granulosa cells. These findings demonstrate that NO and cGMP influence FoxO1 expression possibly through antagonizing the action of FSH in cultured granulosa cells. Results of both immunoblot analysis and immunohistochemistry also show that estradiol implantation do not affect the expression of FoxO1 in rat granulosa cells as gonadotrophins do, indicating that mechanism of estradiol on granulosa cells is different from gonadotrophins. Together, our experiments suggest that expression of FoxO1 in rat granulosa cells can be regulated by gonadotrophins and the NO/cGMP signaling pathway.

Estradiol Replacement Enhances Working Memory in Middle-Aged Rats When Initiated Immediately after Ovariectomy But Not after a Long-Term Period of Ovarian Hormone Deprivation

The goal of the present study was to explore the effects of long-term hormone deprivation on the ability of subsequent estrogen replacement to affect cognition. Female rats, 12 months of age, underwent ovariectomies (n = 30) or sham surgeries (n = 10). Intact rats and 20 ovariectomized rats received cholesterol implants. Ten ovariectomized rats received implants containing 25% estradiol. Five months later, implants were replaced. Half of the ovariectomized rats with cholesterol implants received estradiol implants and half received new cholesterol implants. Rats with estradiol implants received new estradiol implants. Intact rats were ovariectomized and given estradiol implants. Beginning 1 wk later, working memory performance was assessed in an eight-arm radial maze across 24 d of acquisition and during eight additional trials in which a 2.5-h delay was imposed between the fourth and fifth arm choices. Estradiol replacement initiated immediately after ovariectomy at either 12 or 17 months of age significantly improved performance during acquisition and delay trials, compared with control treatment. When estradiol replacement was initiated at 17 months of age, 5 months after ovariectomy, no enhancements were evident. Uteri of rats that experienced delayed estradiol replacement weighed significantly more than uteri of ovariectomized controls but significantly less than uteri of rats that received immediate estradiol replacement. Uterine weight negatively correlated with mean errors during acquisition. These results indicate that whereas chronic estradiol replacement regimens positively affect working memory in middle-aged animals when initiated immediately after ovariectomy, estradiol replacement is not effective when initiated after long-term hormone deprivation.

Diurnal and estradiol-dependent changes in gonadotropin-releasing hormone neuron firing activity

A robust gonadotropin-releasing hormone (GnRH) surge is a prerequisite signal for the luteinizing hormone (LH) surge that triggers ovulation. In rodents, the GnRH surge is initiated by elevated estradiol and a diurnal switch in estrogen action from negative to positive feedback. The ability of constant estradiol treatment to induce daily LH surges was tested in adult mice that were ovariectomized (OVX) or OVX and treated with estradiol implants (OVX+E). LH in OVX mice showed no time-of-day difference. In contrast, OVX+E mice showed a large LH surge (8- to 124-fold relative to the a.m.) in p.m. samples on d 2-5 post-OVX+E. Targeted extracellular recordings were used to examine changes in firing activity of GnRH neurons in brain slices. There was no time-of-day difference in cells from OVX mice. In contrast, OVX+E cells recorded in the p.m. showed an increased mean firing rate and instantaneous firing frequency, which could increase GnRH release, and decreased duration of quiescence between bouts of firing, possibly reflecting increased pulse frequency, compared with cells recorded in the a.m. In the a.m., OVX+E cells showed changes in GnRH neuron firing reflecting negative feedback compared with OVX cells, whereas in the p.m., OVX+E cells exhibited changes suggesting positive feedback. These data indicate that differences in pattern and level of individual GnRH neuron firing may reflect the switch in estradiol action and underlie GnRH surge generation. The persistence of altered GnRH neuron activity in slices indicates that this approach can be used to study the neurobiological mechanisms of surge generation.

Effects of estradiol implantation on growth, carcass traits and circulating concentrations of insulin-like growth factors (IGFs) and IGF-binding protein-3 in finishing barrows

Eighty crossbred barrows aged 120 to 141 days and weighing 71.2±0.8 kg were randomly divided into eight pens, after which each of 40 animals in four pens was implanted with 24 mg of estradiol-17β (E 2; Compudose®). The animals were allowed an unrestricted access to water and a finisher diet containing 16% crude protein and 3.4 Mcal DE/kg and slaughtered at 107.4±0.8 kg. Blood samples were obtained by jugular venipuncture at day 0 before the implantation and at days 21 and 42. Serum concentration of E 2 increased between days 0 and 21 after the implantation and declined to a level above that of day 0 ( P<0.01) by day 42. E 2 implantation caused a decrease ( P<0.01) in feed intake and backfat thickness and a tendency ( P=0.08) of decreased average daily gain. However, feed conversion efficiency (FCE; live weight gain/feed intake) did not change due to the implantation ( P=0.20). The E 2 implantation did not affect physicochemical characteristics of longissimus muscle including percentages of protein ( P=0.17) and fat ( P=0.43), 24-h pH ( P=0.39), drip loss ( P=0.99), L* (lightness; P=0.78) and a* (redness; P=0.49) values. Serum concentration of insulin-like growth factor (IGF)-I decreased between days 0 and 21 ( P<0.01) and also between days 21 and 42 ( P<0.05) in unimplanted pigs, but not in implanted pigs ( P>0.05), which resulted in a greater ( P<0.05) mean IGF-I concentration in the implanted vs. unimplanted group. By contrast, serum concentrations of IGF-II and IGF-binding protein-3 did not differ between the two groups ( P>0.05). In summary, results suggest that E 2 suppresses voluntary feed intake and backfat deposition without significantly affecting growth efficiency and muscle characteristics in barrows and that effects of E 2 may be partly mediated by IGF-I.

Hysterectomy and bilateral oophorectomy for severe premenstrual syndrome.

Premenstrual syndrome (PMS) is a chronic, poorly understood psycho-endocrine disorder severely affecting 5%; of women. Hormonal therapy which suppresses ovulation is the mainstay of medical treatment, but these interventions are rarely permanent. We evaluated the effectiveness and patient satisfaction with total abdominal hysterectomy/bilateral salpingo-oophorectomy (TAH/BSO) in PMS sufferers, and assessed the post-operative HRT continuation. All women undergoing TAH/BSO for severe PMS between January 1994 and April 2000 were interviewed and responses recorded by structured questionnaire. Forty-seven women were interviewed. Median age was 42 years (interquartile range 39.8-46.6) at the time of surgery. They had suffered with PMS for a mean of 9.68 years (SD 6.8) and received treatment for a mean of 3.57 years (SD 2.0) prior to referral to a gynaecologist. Fifty-two percent were treated with estradiol patches and 48% with estradiol implants prior to TAH/BSO. Ninety-six percent of women were 'satisfied' or 'very satisfied' with TAH/BSO, and 93.6% declared complete resolution of their cyclical symptoms; 93.6% were continuing with HRT usually by implants of estradiol and testosterone for a mean duration of 3.8 years (SD 1.86) post-operatively. Despite few reports of TAH/BSO as a treatment for severe PMS, we have found surgery, coupled with appropriate HRT, to be an extremely effective and well-accepted permanent cure for PMS.

Effect of estradiol implants on reproductive behavior of female Lapland longspurs ( Calcarius lapponicus)

The role of estrogens in reproductive behavior of free-living birds has been little investigated, despite the importance of estrogens in coordinating reproductive behavior and the need for information on potential effects of estrogenic contaminants on wildlife. We gave subcutaneous implants of estradiol (E 2) to 15 female Lapland longspurs ( Calcarius lapponicus), an arctic bird with a six-week breeding season. Controls were 9 females with empty implants and 14 unimplanted females. After implantation, E 2 females had greater E 2 levels and greater body mass than controls. We did not detect any increases in, or prolongation of, sexual or nest-building behavior. The incubation period was longer for E 2 nests than for control nests. Nest videotapes showed that E 2 females and their mates exhibited normal nestling care, and nestling growth, fledging success, and overwinter survival were also unaffected. However, whenever the males arrived at the nests, E 2 females showed a significantly greater likelihood of begging from the male rather than leaving the nest. Courtship or incubation feeding have been considered atypical for this species, and it is not clear what role E 2 normally plays in promoting begging behavior. Overall, elevated E 2 levels did not result in any obvious costs for the female, save perhaps for slightly reduced incubation efficiency. The weak response to hormonal implants is similar to patterns seen in male Lapland longspurs, and may be related to the short breeding season. However, since little is presently known about the role of estrogens in behavior of wild female birds, it remains to be seen whether these patterns are typical of female passerines in general, or of short-season breeders. Further research on effects of estrogens (both exogenous and endogenous) on free-living female birds is needed.