The routes of hysterectomy: A survey of current practices amongst members of the International Society for Gynaecologic Endoscopy (ISGE).

OBJECTIVE: This study aimed to explore the current opinion on the routes of hysterectomy amongst the members of the International Society for Gynaecologic Endoscopy (ISGE), as well as the perceptions of potential barriers that inhibit gynaecologists from offering a minimally invasive hysterectomies (MIHs) to their patients. STUDY DESIGN: An anonymous, electronic survey was designed, including the questions about the surgeon location and length of gynaecological practice, preferred approach to hysterectomy, approximate number of surgical cases performed during the year preceding the survey (2021), and potential barriers and contraindications to performing MIHs. It was validated by 12 practicing gynaecologists. Subsequently, the survey was sent to all practicing gynaecologists who are the members of the ISGE. RESULTS: We received a response from 159 members of ISGE (29 % response rate), of which 92 % with ≥ 5 years in practice since the completion of their residency training in Gynaecology and Obstetrics. When asked about the preferred route of hysterectomy for themselves or their relatives, 59 % chose total laparoscopic hysterectomy (TLH), 19 % vaginal hysterectomy (VH), 8 % chose laparoscopically-assisted vaginal hysterectomy (LAVH) and 5 % chose total abdominal hysterectomy (TAH). However, TAH was the most performed hysterectomy procedure undertaken by the respondents in the year preceding the survey. When asked about the main obstacles to performing MIHs, more than half of the respondents highlighted insufficient training during residency and insufficient surgical experience. Only 25 % of the responders acknowledged reading the ISGE guidelines on performing vaginal hysterectomy. CONCLUSIONS: Contrary to a full understanding of the benefits of MIHs, lack of training, as well as insufficient surgical experience and unawareness of existing evidence-based guidelines were the main reasons for the high rate of TAH among the ISGE members who participated in the study. All efforts should be directed at teaching VH and TLH techniques during residency, continuous acquisition of practical experience, and use of validated patient selection guidelines for MIH in daily clinical practice.

Practice of laparoscopic prolapse surgery in Europe - ESGE Survey.

Sacrocolpopexy is considered as the "gold standard" for management of women with apical prolapse. Numerous technical variants are being practiced. The first aim of this survey was to determine the habits of practice of laparoscopic sacrocolpopexy (LSCP) in Europe. The second aim was to determine whether surgeons who perform laparoscopic pelvic organ prolapse (POP) repair are familiar with the practice of alternative techniques and with mesh-less laparoscopic treatment of prolapse. The questionnaire was designed by the Urogynaecology Special Interest Group of the European Society for Gynaecological Endoscopy (ESGE). All ESGE-members were invited by email to respond to this survey consisting of 54 questions divided in different categories. Following review of ESGE member's responses, we have highlighted the great heterogeneity concerning the practice of LSCP and important variability in performance of concomitant surgeries. Alternative techniques are rarely used in practice. Furthermore, the lack of standardisation of the many surgical steps of a laparoscopic sacrocolpopexy is mainly due to the lack of evidence. There is a need for training and teaching in both standard and newer innovative techniques as well as the reporting of medium and long-term outcomes of both standard laparoscopic sacrocolpopexy and any of its alternatives.

The influence of persistent bleeding after supracervical hysterectomy on depressive and anxious symptoms: a prospective bicenter study.

PURPOSE: Postoperative spotting is a frequent adverse symptom after laparoscopic supracervical hysterectomy (LSH). The conical excision (eLSH) reduces the postoperative spotting rate, but data in a larger collective are still rare and inconsistent. The influence of persistent bleeding on the anxious and depressive symptoms has not been analyzed yet. METHODS: 311 patients, who underwent a laparoscopic supracervical hysterectomy with conical excision (n = 163), or with straight cervical resection (n = 148) were included. Anxious and depressive symptoms and postoperative spotting were recorded before operation, at 3 month follow-up and at 1 year follow-up in both operative groups using a validated questionnaire (German version of Hospital Anxiety and Depression Scale, HADS-D) and additional questions concerning the frequency and impact of bleeding. Statistical analysis included the impairment of bleeding as well as its impact on depressive and anxious symptoms for both groups. RESULTS: 11.5% after eLSH and 15.5% after LSH reported spotting after 1 year. Supracervical hysterectomy significantly improves depressive and anxious symptoms at 3 and at 12 month follow-up for both groups (p < 0.001) independent on residual spotting. Patients with a preoperative continuous bleeding showed a maximum benefit independent on operative method. CONCLUSION: Laparoscopic supracervical hysterectomy has a positive effect on anxious and depressive symptoms in the short-term and intermediate-term follow-up. The conical excision of the cervical stump reduces postoperative spotting rate, but has no explicit advantage on symptoms of depression or anxiety, irrespective of residual postoperative spotting.

The influence of conventional and extended supracervical hysterectomy on sexuality and quality of life parameters: a prospective bi-center study with a special focus on postoperative spotting.

PURPOSE: Supracervical as well as total hysterectomy are considered to improve postoperative sexuality as well as quality of life, but the benefit of supracervical hysterectomy (LSH) is impaired in up to 20 percent by postoperative spotting. The aim of this study was to analyze the influence of a conical excision of the cervical stump during supracervical hysterectomy on the postoperative spotting rate and its influence on sexuality and in turn quality of life. METHODS: 321 Patients who underwent a laparoscopic supracervical hysterectomy with conical excision (extended laparoscopic supracervical hysterectomy, eLSH, n = 166, Dormagen hospital) or with straight cervical resection (laparoscopic supracervical hysterectomy, LSH, n = 133, MIC Clinics Berlin) were included. Sexual matters, quality of life parameters and additional questions were recorded before operation, at three months of follow up, and at one year of follow up in both groups using a validated questionnaire (German version of International Consultation on Incontinence Questionnaire Vaginal Symptoms Module, ICIQ_VS). Statistical analysis included the impact and impairment of bleeding on sexuality, quality of life in both groups and co-factors such as vaginal symptoms. RESULTS: 11.3% after eLSH and 15.5% after LSH reported spotting after 1 year. Supracervical hysterectomy significantly improves quality of life and sexuality and a conical excision of the remaining stump is associated with a lower but insignificantly reduced spotting rates. Postoperative spotting has no negative influence on sexual matter score of ICIQ_VS, but reduces the postoperative quality of life focusing on vaginal symptoms in a significant way. CONCLUSION: The improvement of ICIQ_VS scores after supracervical hysterectomy is independent of postoperative spotting, but the quality-of-life score is positively influenced by a reduction in the postoperative spotting rate.

Laparoscopic pectopexy: a follow-up cyclic biomechanical analysis determining time to functional stability.

INTRODUCTION: Pectopexy, a laparoscopic method for prolapse surgery, showed promising results in previous transient testing by this group. It was shown that a single suture, yielding an ultimate load of 35 N, was equivalent to continuous suturing. This was demonstrated in an in vitro cadaver study. This transient data were used to establish an elastic stress-strain envelope. It was now possible to proceed to dynamic in vitro analysis of this surgical method to establish time to functional stability. METHODS: Cyclic testing of this fixation method was performed on human female embalmed cadaver (cohort 1) and fresh, non-embalmed cadaver (cohort 2) pelvises. The testing envelope was 5-25 N at a speed of 1 mm/s. 100 load regulated cycles were applied. RESULTS: 100 cycles were completed with each model; no overall system failure occurred. Steady state, i.e., functional stability was reached after 14.5 (± 2.9) cycles for the embalmed group and after 19.1 (± 7.2) cycles for the non-embalmed group. This difference was statistically significant p = 0.00025. CONCLUSION: This trial showed in an in vitro cyclic testing of the pectopexy method that functional stability may be achieved after no more than 19.1 cycles of load exposure. When remaining within the established load envelope of below 25 N, patients do not need to fear global fixation failure. Testing did demonstrate differences in non-embalmed and embalmed cadaver testing. Embalmed cadaver testing tends to underestimate time to steady state by 26.3%.

Relation between plasma trough concentration of abiraterone and prostate-specific antigen response in metastatic castration-resistant prostate cancer patients.

BACKGROUND: Abiraterone (ABI) is a major oral agent for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients but its systemic exposure is subject to a large inter-individual variability. We aimed to explore the relationship between ABI trough plasma concentration and prostate-specific antigen (PSA) response in mCRPC patients and to identify the critical determinants for its activity. PATIENTS AND METHODS: This is a monocentric prospective observational study in mCRPC patients treated with ABI. The plasmatic concentration of ABI at steady state was measured using liquid chromatography with fluorescence detection. The primary objective was to study the relationship between mean ABI plasma exposure (ABI Cmin) and 3-month PSA response. RESULTS: From 2012 to 2016, 61 mCRPC patients were eligible for pharmacokinetic/pharmacodynamic assessment. Thirty-eight patients experienced PSA response (62%, [confidence interval {CI} 95% 50-78]). In univariate analysis, ABI Cmin was 1.5-fold higher in responders: 12.0 ng/mL (CI 95% 9.4-15.6) versus 8.0 ng/mL (CI 95% 5.8-11.6; P = 0.0015). In multivariate analysis, only ABI Cmin was independently associated with PSA response (odds ratio = 1.12 [CI 95% 1.01-1.25], P = 0.004). By receiver operating characteristic analysis, the optimal threshold for ABI Cmin was 8.4 ng/mL. Progression-free survival (PFS) was significantly higher in patients with ABI Cmin above 8.4 ng/mL (hazard ratio 0.55, [CI 95% 0.31-0.99], 12.2 [CI 95% 9.2-19.5] versus 7.4 [CI 95% 5.5-14.7] months otherwise, P = 0.044). CONCLUSIONS: We showed that ABI trough concentration correlates with PSA response and PFS. Moreover, we could determine a cut-off value of plasmatic concentration for PSA response. Altogether, ABI concentration monitoring appears as a new approach to improve clinical outcome in mCPRC patients.

Laparoscopic Pectopexy: A Biomechanical Analysis.

INTRODUCTION: Pectopexy, a laparoscopic method for prolapse surgery, showed promising results in recent literature. Further improving this approach by reducing surgical time may decrease complication rates and patient morbidity. Since laparoscopic suturing is a time consuming task, we propose a single suture /mesh ileo-pectineal ligament fixation as opposed to the commonly used continues approach. METHODS: Evaluation was performed on human non-embalmed, fresh cadaver pelves. A total of 33 trials was performed. Eight female pelves with an average age of 75, were used. This resulted in 16 available ligaments. Recorded parameters were ultimate load, displacement at failure and stiffness. RESULTS: The ultimate load for the mesh + simplified single "interrupted" suture (MIS) group was 35 (± 12) N and 48 (± 7) N for the mesh + continuous suture (MCS) group. There was no significant difference in the ultimate load between both groups (p> 0.05). This was also true for displacement at failure measured at 37 (± 12) mm and 36 (±5) mm respectively. There was also no significant difference in stiffness and failure modes. CONCLUSION: Given the data above we must conclude that a continuous suture is not necessary in laparoscopic mesh / ileo-pectineal ligament fixation during pectopexy. Ultimate load and displacement at failure results clearly indicate that a single suture is not inferior to a continuous approach. The use of two single sutures may improve ligamental fixation. However, overall stability should not benefit since the surgical mesh remains the limiting factor.

Vemurafenib pharmacokinetics and its correlation with efficacy and safety in outpatients with advanced BRAF-mutated melanoma.

Vemurafenib is a BRAF kinase inhibitor approved for first-line treatment of metastatic BRAF (V600) -mutant melanoma. However, data on the pharmacokinetic/pharmacodynamic (PK/PD) relationship are lacking. The aim of this prospective, multicenter study was to explore the PK/PD relationship for vemurafenib in outpatients with advanced BRAF-mutated melanoma. Fifty-nine patients treated with single-agent vemurafenib were prospectively analyzed. Vemurafenib plasma concentration (n = 159) was measured at days 15, 30, 60, and 90 after treatment initiation. Clinical and biological determinants (including plasma vemurafenib concentration) for efficacy and safety were assessed using Cox's model and multivariate stepwise logistic regression. Median progression-free survival (PFS) and overall survival were 5.0 (95 % confidence interval [95 % CI] 2.0-6.0) and 11.0 (95% CI 7.0-16.0) months, respectively. Twenty-nine patients (49 %) experienced any grade ≥3 toxicity and the most frequent grade ≥2 toxicity was skin rash (37 %). Severe toxicities led to definitive discontinuation in seven patients (12 %). Grade ≥2 skin rash was not statistically associated with better objective response at day 60 (p = 0.06) and longer PFS (hazard ratio 0.47; 95 % CI 0.21-1.08; p = 0.075). Grade ≥2 skin rash was statistically increased in patients with ECOG ≥ 1 (odds ratio 4.67; 95 % CI 1.39-15.70; p = 0.012). Vemurafenib concentration below 40.4 mg/L at day 15 was significantly associated with a shorter PFS (1.5 [0.5-5.5] vs. 4.5 [2-undetermined] months, p = 0.029). Finally, vemurafenib concentration was significantly greater in patients developing grade ≥2 rash (61.7 ± 25.0 vs. 36.3 ± 17.9 mg/L, p < 0.0001). These results suggest that early plasma drug monitoring may help identify outpatients at high risk of non-response or grade ≥ 2 skin rash.

Fermi-edge superfluorescence from a quantum-degenerate electron-hole gas.

Nonequilibrium can be a source of order. This rather counterintuitive statement has been proven to be true through a variety of fluctuation-driven, self-organization behaviors exhibited by out-of-equilibrium, many-body systems in nature (physical, chemical, and biological), resulting in the spontaneous appearance of macroscopic coherence. Here, we report on the observation of spontaneous bursts of coherent radiation from a quantum-degenerate gas of nonequilibrium electron-hole pairs in semiconductor quantum wells. Unlike typical spontaneous emission from semiconductors, which occurs at the band edge, the observed emission occurs at the quasi-Fermi edge of the carrier distribution. As the carriers are consumed by recombination, the quasi-Fermi energy goes down toward the band edge, and we observe a continuously red-shifting streak. We interpret this emission as cooperative spontaneous recombination of electron-hole pairs, or superfluorescence (SF), which is enhanced by Coulomb interactions near the Fermi edge. This novel many-body enhancement allows the magnitude of the spontaneously developed macroscopic polarization to exceed the maximum value for ordinary SF, making electron-hole SF even more "super" than atomic SF.

Effect of single post-ovulatory administration of levonorgestrel on gene expression profile during the receptive period of the human endometrium.

The hypothesis that levonorgestrel (LNG) used as an emergency contraceptive interferes with endometrial receptivity remains unproven. We compared the endometrial gene expression profile during the receptive period after administering a single dose of LNG 1.5 mg or placebo on day 1 of the luteal phase. An endometrial biopsy was done on day LH+7 or LH+8 and samples were taken from seven volunteers, each one contributing with one cycle treated with placebo and another with LNG. The expression of 20 383 genes was determined using cDNA microarrays. Real-time RT-PCR was used 1) to confirm the differences found in DNA microarray analysis and 2) to determine the effect of LNG on transcript levels of C3, C4BPα, COX2, MAOA, S100A4, and SERPINB9, known to be upregulated during receptivity, and on cPLA2α, JAK1, JNK1, CTSL1, and GSTP1, known to respond to mifepristone. Additional endometrial biopsies were done during the pre-receptive (LH+3) and receptive (LH+7) period and samples were taken from eight untreated volunteers in order to determine the changes associated with acquisition of receptivity of 14 genes. Mean levels of PAEP, TGM2, CLU, IGF2, and IL6ST mRNAs increased after administering LNG while those of HGD, SAT1, EVA1, LOC90133, ANXA1, SLC25A29, CYB5A, CRIP1, and SLC39A14 decreased. Except for the level of ANXA1 transcript, all changes remained within the range observed in untreated controls, and none of the transcripts responding to mifepristone changed in response to LNG. Post-ovulatory administration of LNG caused minimal changes in gene expression profiling during the receptive period. Neither the magnitude nor the nature or direction of the changes endorses the hypothesis that LNG interferes with endometrial receptivity.

Endometrial effect of progesterone delivered by vaginal rings in estrogen-treated postmenopausal women.

AIM: The type of estrogen and progestin as well as their doses, route and regimens of administration may each affect the benefit-risk profile of postmenopausal hormone therapy. The aim of this study was to evaluate the endometrial effect of progesterone released continuously from a vaginal ring, combined with transdermal estradiol in postmenopausal women. METHOD: Forty-four postmenopausal women participated in a randomized, double-blind, dose-finding study evaluating two hormonal treatments, combining 50 microg/day of estradiol delivered by transdermal patches and either 0.5-g or 1-g progesterone vaginal rings (PVR) given for 12 weeks. The effect on the endometrium was assessed by histology and the detection of the proliferative marker Ki-67. We also measured the serum concentration of estradiol and progesterone, the tissue concentration of progesterone and the immunolocalization of estradiol and progesterone receptors in the endometrium. RESULTS: Endometrial thickness was increased after both treatments, although endometrial histology appeared atrophic in most biopsies. A circulating dose-response of serum progesterone levels was observed from the first to the 12th week of PVR use. In the high-progesterone-dose group, the scarce presence of Ki-67 and hormone receptors reflected the predominant action of progesterone in endometrial glands and stroma, in parallel with a lower tissue concentration of progesterone in this group. CONCLUSION: The PVR appears to be a promising method of administering natural progesterone to postmenopausal women treated with estrogen. Estradiol levels corrected the menopausal symptoms, as expected, and the presence of atrophic endometrium in the majority of women indicated that both doses of progesterone oppose the stimulatory estradiol effects, although the percentage of proliferative tissue was not negligible in both groups.

Phase diagram of a two-dimensional lattice gas model of a ramp system.

Using Monte Carlo simulation and fundamental measure theory we study the phase diagram of a two-dimensional lattice gas model with a nearest neighbor hard core exclusion and a next-to-nearest neighbor finite repulsive interaction. The model presents two competing ranges of interaction and, in common with many experimental systems, exhibits a low density solid phase, which melts back to the fluid phase upon compression. The theoretical approach is found to provide a qualitatively correct picture of the phase diagram of our model system.

Acidic pH and increasing [Ca(2+)] reduce the swelling of mucins in primary cultures of human cervical cells.

BACKGROUND: Cervical mucus is a heterogeneous mixture of water, ions and mucins that form a hydrophilic polymer gel. Mucins, the main components of mucus, are condensed inside secretory granules and swell to become a hydrogel after exocytosis. Using human cervical secretory cell primary cultures, the effect of [Ca(2+)] and [H(+)] on the swelling velocity of mucin granules was investigated in vitro. METHODS AND RESULTS: Immunocytochemistry demonstrated that estrogen and progesterone receptors were expressed in cultured secretory cells along with mucins type 1, 4, 5AC and 5B. Exocytosis of secretory cells, recorded by videomicroscopy, showed that during swelling, the radius of the secretory granule matrix followed first-order kinetics. An increase in extracellular [Ca(2+)] from 1 to 4 mmol/l or a reduction in pH from 7.4 to 6.5 was seen to produce a significant decrease in the velocity of swelling of the secretory granule matrix. CONCLUSIONS: The inverse relationship observed between the diffusion of the granular matrix and the extracellular [Ca(2+)] or [H(+)] suggested that changes in cation concentration might drastically affect the swelling characteristics of mucins and provide a control mechanism for the observed viscoelastic properties of mucus.

Gonadotrophin and testosterone suppression by 7alpha-methyl-19-nortestosterone acetate administered by subdermal implant to healthy men.

The synthetic androgen 7alpha-methyl-19-nortestosterone (MENT) is a potent suppressor of gonadotrophin that has several advantages for long term administration to normal or hypoandrogenic men. The aim of this study was to examine MENT serum concentrations following subdermal insertion of MENT acetate (MENT Ac) implants and their effects on gonadotrophins, testosterone, dihydrotestosterone (DHT), sex hormone-binding globulin, prostate specific antigen and insulin-like growth factor-1 serum concentrations in normal men. A total of 45 healthy men were recruited at three clinics. Each subject received one, two or four implants for 28 days. Serum samples were obtained before insertion and on days 8, 15, 22, 29, 36 and 43 after implant insertion. The average daily dose delivered in vivo by one implant was approximately 500 microg. One, two or four MENT Ac implants produced dose dependent and sustained serum MENT concentrations for the entire duration of treatment of 0.7 +/- 0.1, 1.2 +/- 0.1 and 2.0 +/- 0.1 nmol/l respectively. This treatment induced a dose dependent decrease in gonadotrophin and androgen serum levels. Two and four implants induced maximal suppression that was maintained throughout treatment and was completely reversed after removal of the implants. The mean decreases were 93 +/- 1% for testosterone, 80 +/- 3% for DHT, 97 +/- 1% for luteinizing hormone and 95 +/- 1% for follicle stimulating hormone. No serious adverse reactions were reported by the volunteers and no consistent changes in clinical chemistry and haematology were found. These results indicate that MENT Ac implants are an efficient way of MENT administration and confirm the potent gonadotrophin and androgen suppressive effect of this drug.

Sex hormone binding globulin expression and colocalization with estrogen receptor in the human Fallopian tube.

The detection of sex hormone binding globulin (SHBG) or SHBG mRNA in several sex steroid target tissues, has raised the possibility that SHBG modulates the action of sex steroids outside the vascular compartment. The presence of SHBG mRNA was investigated by RT-PCR in the poly (A+) RNA fraction of the human Fallopian tube. Human and rat liver were used as positive and negative control tissues, respectively. The electrophoretic analysis of the amplified PCR products showed bands at 219 bp, corresponding to the expected size of the SHBG cDNA, in the Fallopian tube and human liver but not in rat liver, indicating that SHBG might be synthesized by the Fallopian tube. The cellular localization of SHBG and of estrogen receptor (ER) was examined by immunohistochemistry in consecutive sections of Fallopian tube tissues for individual staining or double immunostaining in the same section. Specific immunostaining of SHBG was present in the epithelial, vascular and muscle cells of the ampullary and isthmic region. In epithelial cells, immunoreactive SHBG was present in the apical end with the highest concentration close to the luminal membrane. The ER was localized in the nuclei of epithelial, stromal and muscle cells of the ampulla and isthmus. Double immunostaining showed that SHBG and ER are colocalized principally in epithelial cells of the ampulla and in muscle cells of the isthmus. In conclusion, the detection of SHBG and SHBG mRNA and the localization of SHBG in estrogen target cells was shown. These findings support the hypothesis that SHBG might regulate sex steroid action at the tissue level.

[Erythropoietin]. / Erythropoietin.

The production of red cells can be stimulated by pharmacologic doses of recombinant human erythropoietin (rHu-EPO), provided EPO-sensitive precursors and iron are available. Its side effects are negligible when used in patients with nonrenal anemia. Antibodies against rHu EPO are a rare event. Iron supplementation is routinely necessary in patients with low iron stores, since availability of iron is a rate-limiting cofactor for red cell production. The rationale for treating patients with anemia of cancer or chronic inflammation is to avoid homologous blood transfusion. However, it is not proven whether a raising of the hemoglobin concentration by 2 or 3 g% will improve the quality of life in these multimorbid patients who undergo palliative treatment. There is no evidence yet that rHu-EPO has reduced morbidity and mortality in such patients. Another question is the cost effectiveness of EPO particularly in patients who suffer from an incurable disease. EPO has also been used as an adjuvant in autologous preoperative transfusion programs and has increased the available volume of red cells for transfusion particularly in conjunction with intravenous iron supplementation. EPO given for 14 days preoperatively in patients with elective hip replacement reduced the need for transfusion by nearly 50%. A high dose of oral ferrous sulfate (300 mg) was given 11 days in advance of rHu EPO. Randomized trials are needed for patients with an initial low Hb (< 13.5 g/dl) to study the efficacy and cost effectiveness of different strategies avoiding homologous transfusion and also the risk-benefit ratio of such strategies versus homologous transfusions, since the risk of homologous transfusions has decreased considerably in recent years.

Increased sensitivity and accumulation of estradiol in the rat oviduct during early pregnancy.

We have previously reported that a single injection of estradiol-17 beta (E2) given on day 3 of pregnancy (P3) is far more effective for accelerating oviductal transport in the rat, than treatment given on day 1 (P1). In order to quantify this change, dose-response curves were established for six different doses of E2 (range 0.031 to 1.00 micrograms per animal) given on P1, P2 or P3. In addition, a possible mechanism was explored by comparing the plasmatic and oviductal levels of E2 between 30 and 180 min following treatment with E2 on P1 or P3. As the interval from ovulation to treatment was increased, the transport of a larger number of embryos was accelerated and a smaller dose was required. The minimal effective dose decreased 30-fold from P1 to P3, the oviducts accumulated 20% to 90% more E2 on P3 than on P1, tissue levels were 6- to 48-fold higher than plasma levels and the latter did not differ between P1 and P3. It is concluded that the oviduct exhibits increased sensitivity and responsiveness to E2 on P3 and this is associated with greater accumulation of the hormone in the organ, not attributable to higher E2 plasma levels.

Increased sensitivity and accumulation os estradiol in the rat oviduct during early pregnancy

We have previously reported that a single injection of estradiol-17 beta (E2) given on day 3 of pregnancy (P3) is far more effective for accelerating oviductal transport in the rat, than treatment given on day 1 (P1). In order to quantify this change, dose-response curves were established for six different doses of E2 (range 0.031 to 1.00 micrograms per animal) given on P1, P2 or P3. In addition, a possible mechanism was explored by comparing the plasmatic and oviductal levelsof E2 between 30 and 180 min following treatment with E2 on P1 or P3. As the interval from ovulation to treatment was increased, the transport of a larger number of embryos was accelerated and a smaller dose was required. The minimal effective dose decreased 30-fold from P1 to P3, the oviducts accumulated 20 percent to 90 percent more E2 on P3 than on P1, tissuelevels were 6- to 48-fold higher than plasma levels and the latter did not differ between P1 and P3. It is concluded that the oviduct exhibits increased sensitivity and responsiveness to E2 on P3 and this isassociated with greater accumulation of the hormone in the organ, not attributable to higher E2 plasma levels

Tissue uptake of human sex hormone-binding globulin and its influence on ligand kinetics in the adult female rat.

The distribution of human sex hormone-binding globulin (hSHBG) and its influence upon the kinetics of its ligands were assessed in the adult female rat, which lacks a comparable protein in serum. Purified hSHBG was administered i.v. to adult female rats as a single bolus. The plasma disappearance rate of immunoreactive hSHBG had one component with a half-life of 15 h. The estradiol (E2) binding activity of serum attributable to hSHBG was elevated 2-fold; during a continuous infusion of E2, hSHBG increased E2 serum levels above those of control infused animals. Treatment with hSHBG did not modify the plasma clearance of endogenous E2, but accelerated the disappearance rate of 5 alpha-dihydrotestosterone (DHT). In animals injected with a tracer dose of radioactive steroids, pretreatment with hSHBG increased uterine and oviductal accumulation of E2- but not DHT-associated radioactivity. This effect was specific to some E2 target tissues since hSHBG did not alter the concentration of E2- or DHT-associated radioactivity in the hypophysis, liver, diaphragm, or brain. Treatment with anti-E2 antibodies, which elevated E2 binding activity in serum, decreased the accumulation of E2-associated radioactivity in uterus and oviduct. Immunofluorescent localization of hSHBG revealed intense labeling of the uterine and oviductal epithelium. We conclude that this foreign hormone-binding globulin introduced in serum at concentrations that have minimal circulating reservoir effect on E2 can reach intracellular domains and affect the concentration of this ligand in target tissues.