Effect of exogenous oestrogen treatment frequency on induction of artificial lactation in pseudopregnant sows.

In this study, we examined whether the frequency of exogenous oestrogen treatment affects the induction of artificial lactation and milk production. Furthermore, we analysed changes in milk components obtained from artificially lactating sows. Pseudopregnant induced by treatment with 30 mg of estradiol dipropionate (EDP) on Day 10 (Day 0 = the last day of estrus) were divided into three groups: those administered 5 mg of EDP once on Day 39 (n = 5), twice on Days 32 and 39 (n = 5) and three times on Days 25, 32 and 39 (n = 6). All animals were treated with prostaglandin F2α (PGF2α) on Day 46 for induced lactation. Artificial lactation was induced in 66.7%-80.0% of sows, and the EDP treatment frequency before PGF2α administration had no significant effect on either the induction rate of artificial lactation or the milk yield during the experimental period. The milk composition (levels of crude protein, crude fat, crude ash, lactose and immunoglobulin) did not differ among the groups. In conclusion, the number of EDP treatments prior to PGF2α administration had no effect on either the efficiency of artificial lactation induction or milk production.

Effect of prostaglandin alone and in combination with trace minerals on the follicular and luteal dynamics, estrus response and pregnancy in sub-estrus buffaloes (Bubalus bubalis).

Sub-estrus is a condition when buffaloes do not display behavioural estrus signs, despite being in estrus and causes a delay in conception and increases the service period. The present study describes the effect of synthetic prostaglandin (PGF2α) alone and in combination with trace minerals on the follicular and corpus luteum (CL) dynamics, serum estradiol (E2) and progesterone (P4) concentration correlating estrus response and pregnancy outcome in sub-estrus buffaloes during the breeding season. A total of 50 sub-estrus buffaloes, identified through ultrasonography (USG) examination, were randomly allocated into three groups, viz. T1 (Synthetic PGF2α, Inj. Cloprostenol 500 µg, i.m, n = 17), T2 (Synthetic PGF2α + Trace mineral supplementation, Inj. Stimvet 1 mL/100 kg body weight, i.m., n = 17) and control (untreated; n = 16). Following treatment, 100% of sub-estrus buffaloes were induced estrus in the T1 and T2 groups, while only 18.75% were induced in the control. The CL diameter and serum P4 concentration were significantly lower at post-treatment, whereas the pre-ovulatory follicle (POF) size and serum E2 concentration were significantly higher in the T1 and T2 groups as compared to the control (p < .05). The buffaloes of the T2 group had a greater proportion of moderate intensities estrus than those of T1. Moreover, the proportion of buffaloes conceived in the T1 and T2 were 41.2% and 52.95%, respectively. The larger POF diameter and higher serum E2 concentration were associated with intense intensity estrus and higher conception rate (66.7%) in sub-estrus buffaloes. Similarly, CL regression rate, POF size and serum E2 concentration were relatively higher in the buffaloes conceived as compared to those not conceived. It is concluded that synthetic PGF2α in combination with trace minerals induces moderate to intense intensities estrus in a greater proportion of sub-estrus buffaloes and increases the conception rate during the breeding season. Moreover, behavioural estrus attributes correlating follicle and luteal morphometry, serum E2 and P4 concentration could be used to optimise the breeding time for augmenting the conception rate in sub-estrus buffaloes.

A randomized clinical trial of transdermal (gel) versus oral estrogen for endometrial preparation in frozen embryo transfer cycle.

OBJECTIVE: The aim of this study was to compare endometrial thickness with the use of transdermal estrogen (gel) versus oral estrogen (pills) for endometrial preparation in the frozen embryo transfer cycle and serum estrogen concentrations during the preparation cycle, side effects, and chemical and clinical pregnancy rates. METHODS: This was a prospective, randomized controlled trial of women undergoing endometrial preparation for cryopreserved blastocyst transfer. A total of 88 women were randomized, of which 82 completed the study protocol. Of this group, 44 received 6 mg/day of estradiol valerate orally (pills group) and 38 received 4.5 mg/day of estradiol hemihydrate transdermally (gel group). Endometrial thickness was measured using transvaginal ultrasound between the 7 and 10th day of the cycle. Serum estradiol concentrations were measured on the day of initiating the cycle, on control transvaginal ultrasounds, and on the day of embryo transfer. Side effects were documented at each study visit. p<0.05 were adopted as statistically significant. The groups were compared using Student's t-test for continuous variables and chi-square or Fisher's exact test for categorical variables. RESULTS: There were no significant group differences (p>0.05) in endometrial thickness, biochemical and clinical pregnancy rates, miscarriage rate, blood estradiol concentrations, duration of estradiol administration, or cycle cancellation rates. CONCLUSION: Endometrial preparation with transdermal estrogen yielded similar reproductive outcomes to oral estrogen with fewer side effects.

Melatonin administration during the first half of pregnancy improves physiological response and reproductive performance of rabbits under heat stress conditions.

Context Melatonin may have a heat-stress-alleviating role during pregnancy. Aims To investigate the effects of melatonin administration during the first half of pregnancy on heat-tolerance capacity and pregnancy outputs of naturally heat-stressed rabbits. Methods Forty female rabbits were stratified equally into two experimental groups and daily received 1mg melatonin/kg body weight or not (control) for 15 consecutive days post-insemination. Heat tolerance indices, hormone profile, ovarian structures, and fetal loss were determined. Key results Treatment with melatonin significantly decreased respiration rate and rectal temperature, improved concentrations of nitric oxide, and tended to decrease malondialdehyde concentrations (P =0.064) compared to control. Melatonin treatment significantly increased concentrations of high-density lipoprotein, oestradiol, and progesterone compared to control. No significant differences in the numbers of visible ovarian follicles, corpora lutea, and total implantation sites on day 18 of pregnancy were observed between experimental groups. However, melatonin treatment significantly reduced the number of absorbed implantation sites and significantly improved amniotic fluid volume and conception rate compared to control. Conclusions Melatonin administration during the first half of pregnancy can improve reproductive performance of heat-stressed female rabbits. Implications Melatonin can improve fetal survivability via improving heat-tolerance capacity of does and steroidogenesis.

Impact of 17ß-estradiol administration at the moment of timed-AI in Nelore cows with small dominant follicle or not showing estrus.

We aimed to evaluate the effects of administering estradiol (E-17ß) at the moment of timed-AI (TAI) on uterine gene expression, estrous expression rate (EER), and pregnancy rate (P/TAI) in Nelore cows with a small dominant follicle (DF) or not showing estrus at TAI. In Experiments 1 and 2 (Exp1, Exp2) cows were submitted to a P4/E-17ß-based protocol (day 0) for synchronization of ovulation. On day 7, devices were removed, cows received 1 mg E-17ß cypionate and 12.5 mg dinoprost. On day 9, cows with DF < 11.5 mm in diameter were split into different groups. In Exp1 (n = 16/group): Control (no treatment), E-2 (2 mg E-17ß) and E-4 (4 mg E-17ß). In Exp2: Control (n = 12); E-2 (n = 14); GnRH (0.1 mg gonadorelin acetate, n = 13); and E-2+GnRH (association of GnRH and E-17ß, n = 13). Between days 9 and 11, endometrial thickness (ET), time of ovulation detection, and EER were recorded. In Exp1, a uterine cytological sample was collected 4 h after treatment to evaluate the transcript expression of receptors for E-17ß (ESR1 and ESR2), oxytocin (OXTR), and P4 (PGR). In Experiment 3 (Exp3), 3829 suckled cows were submitted to a P4/E-17ß-based protocol for TAI. On day 9, devices were removed and cows received 1 mg E-17ß cypionate and 0.4 mg sodium cloprostenol. On day 11, TAI was performed and cows that did not demonstrate estrus received 0.1 mg gonadorelin acetate, and were allocated into two groups: GnRH (n = 368) and E-2+GnRH (2 mg E-17ß; n = 363). In Exp1, plasma E-17ß concentrations increased at 4 h after treatment in a dose-dependent manner but reduced at 12 h. The E-17ß-treated cows had greater transcript abundance for OXTR and lesser for ESR1 and ESR2, and the ET was reduced 12 h after treatment (P < 0.05). No significant difference (P > 0.1) was observed between the E-17ß doses in estrus or ovulation rate. In Exp2, the interval from treatment to ovulation was longer (P < 0.05) in the E-17ß group. GnRH-treated cows showed higher ovulation rates (89 vs. 35 %) compared to cows not treated with GnRH, as E-17ß-treated cows (P < 0.01) had a lower ovulation rate compared to those not receiving E-17ß (44 vs. 78 %). In Exp3, P/TAI was 55 % for cows in estrus. For those not showing estrus, no difference (P > 0.1) in P/TAI was observed between GnRH (34 %) and E-2+GnRH (31 %) groups. Cows with a DF ≥ 11 mm (n = 192) had a greater (P < 0.05) P/TAI (49 %) than those with DF < 11 mm (n = 377; 29 %). In conclusion, E-17ß administration in the moment of TAI modulates the mRNA expression of uterine receptors in cows with a small DF but does not impact the P/TAI compared with GnRH treatment in suckled Nelore not showing estrus previous to TAI.

Biochemical profile and oocyte quality of primiparous Bos indicus cows submitted to a timed artificial insemination protocol.

The objective of this study was to verify the causes of the lower response of primiparous Bos indicus cows to the ovulation synchronization protocol. Two experiments were performed to evaluate the biochemical profile, oocyte and follicular cell quality (Experiment 1) and pregnancy (Experiment 2). In Experiment 1, suckled primiparous (n = 24) and multiparous cows (n = 24) were submitted to ovum pick up (OPU). On Day 0 (D0), all cows received 2 mg of estradiol benzoate (EB) and an intravaginal progesterone insert (P4). Five days (D5) after the first hormonal administration (EB + P4), all follicles larger than 3 mm were counted on each ovary, and ovum pick-up (OPU) was performed. On day 12 (D12), the intravaginal progesterone insert was removed, and measurement and aspiration of the largest follicle were performed. Blood samples were collected on D5 and D12 to evaluate the concentrations of glucose, cholesterol, NEFA, IGF-1 and insulin. In Experiment 2, suckled primiparous (n = 50) and multiparous (n = 50) cows were subjected to an ovulation synchronization protocol based on E2/P4 (D0: 2 mg EB plus P4 intravaginal insert; D8: 500 µg of cloprostenol, 1 mg cypionate estradiol and 300UI of eCG; D10: artificial insemination). In addition, blood samples were collected on D10 for evaluation of the same hormones and metabolites described in Experiment 1. In all studies, calves remained with the cows during the experimental period. In experiment 1, the number of oocytes grade 1 (P = 0.83), grade 2 (P = 0.23) and grade 3 (P = 0.51), total number of retrieved oocytes (P = 0.14), oocyte quality index (P = 0.93) and total viable oocytes (P = 0.38) did not differ between primiparous and multiparous cows. The number of follicles at the time of follicular aspiration (20.7 ± 1.5 vs. 18.0 ± 1.9; P = 0.05) and the diameter of the largest follicle on D12 (13.5 ± 0.6 vs. 11.4 ± 0.6; P = 0.04) were greater in multiparous cows, and the number of degenerated oocytes was greater in primiparous cows (1.9 ± 0.7 vs. 1.2 ± 0.3; P = 0.05). On D5, the concentrations of IGF-1 (P = 0.47), insulin (P = 0.08), total cholesterol (P = 0.47), NEFA (P = 0.77) and glucose (P = 0.55) in the blood and IGF-1 (P = 0.97) and insulin (P = 0.11) in the follicular fluid did not differ between parity groups. On D12, there was no difference in the concentrations of IGF-1 (P = 0.26), total cholesterol (P = 0.32), NEFAs (P = 0.31) and glucose (P = 0.93) in the blood between primiparous and multiparous cows, however, the serum insulin concentration (P = 0.04) was higher in primiparous cows. There was no correlation between serum and follicular fluid insulin concentrations (r = 0.17; P = 0.31), however, there was a low correlation between serum and follicular fluid IGF-1 concentrations (r = 0.47; P = 0.002). Quantification of transcripts did not differ between parity groups. In experiment 2, concentrations of NEFA (P = 0.12) and insulin (P = 0.16) in the blood and P/AI (P = 0.93) did not differ between parity [60 % (30/50) primiparous vs. 60 % (30/50) multiparous]. In contrast, blood concentrations of IGF-1 (P = 0.0001), total cholesterol (P = 0.005) and glucose (P = 0.01) were greater in primiparous cows. It was concluded that the oocyte quality and expression of the genes evaluated in the granulosa cells were not different between primiparous and multiparous cows. Unexpectedly, the pregnancy rate did not differ between parity. Nevertheless, the blood concentrations of IGF-1, total cholesterol and glucose were greater in primiparous cows.

Optimizing ReBreed21 II: Fertility and reproductive efficiency in different parities during a shortened breeding season in beef cattle.

This study evaluated the efficiency of a rapid reinsemination program allowing timed AI (TAI) every 21d (ReBreed21) in a commercial beef cow-calf operation. Nelore females from different parities (n = 2085) were synchronized for first TAI (D0 = TAI) using an estradiol/progesterone (E2/P4) protocol and assigned to one of three reinsemination programs: Resynch33 (n = 753), traditional resynch program with second TAI at D42 after first TAI; ReBreed21 (n = 687); or ReBreed21+EC (n = 670). The ReBreed females (n = 1357) received intravaginal P4 insert on D12, on D19 P4 was removed, and a dose of equine chorionic gonadotropin (eCG) was administered, then, ReBreed21 females received 0.6 mg of EC (ReBreed21+EC) or nothing (ReBreed21) and on D21, nonpregnancy (NP) was determined using Doppler ultrasound to detect corpus luteum (CL) blood flow (BF) (NP: <25 % BF pixels of total CL area) and NP cows received immediate TAI and GnRH to induce ovulation. Pregnancy diagnosis was performed at D33 after TAI following all TAIs. Cows considered pregnant at D21, based on CL BF, but NP on D33 were designated False-Positives (FP) and false negatives (FN) were number of nonpregnant cows/heifers on d21 based on the CL BF found to subsequently be pregnant on D33 divided by the total number pregnant. Pregnancy/AI (P/AI) did not differ for the first TAI (55.1 %) among the treatments. Heifers had similar P/AI at the second AI in all groups and similar to the first AI. Primiparous had greater P/AI in ReBreed21+EC and Resynch33 at s TAI compared to ReBreed21, 51.7 %, 55.8 %, 34.2 %, respectively. Multiparous had greater P/AI at second TAI in Resynch33 (60.9 %) than ReBreed21 programs (34.7 %). The percentage FP and FN among ReBreed21 programs did not differ, 13.8 and 0.2 %, respectively. Overall accumulative pregnancies on D21 of the breeding season were greater for ReBreed21 and ReBreed21+EC than Resynch33 (69.7 %, 71.6 %, and 55.5 %, respectively). However, on D42 of the breeding season, only heifers had greater pregnancies in ReBreed21 programs than Resynch33 (73.3 %, 74.3.6 %, and 63.2 %, respectively). Average days to pregnancy were less (P = 0.01) for ReBreed21 and ReBreed21+EC than Resynch33. Thus, the ReBreed21 strategy can improve the efficiency of TAI programs in beef cattle. Of interest, ReBreed21 was particularly effective in nulliparous, somewhat effective in primiparous when EC was added to the program, but relatively ineffective in multiparous beef cattle.

Effect of hormone therapy on blood pressure and hypertension in postmenopausal women: a systematic review and meta-analysis.

IMPORTANCE: Menopausal hormone therapy (HT) includes a wide variety of hormonal compounds, and its effect on blood pressure is still uncertain. OBJECTIVE: The aim of this study was to assess evidence regarding the effect of HT on blood pressure in postmenopausal women and its association with arterial hypertension. EVIDENCE REVIEW: This systematic review and meta-analysis included randomized clinical trials and prospective observational studies. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and the incidence of hypertension were assessed. All stages were independently performed by two reviewers. For blood pressure outcome, standardized mean differences (SMD) and 95% confidence intervals (95% CI) were calculated as effect measures. Heterogeneity was assessed using the I2 statistic. The results are presented based on the HT type. The incidence of hypertension was compared using descriptive analyses. FINDINGS: Eleven studies were included with 81,041 women evaluated, of which 29,812 used HT. The meta-analysis, conducted with 8 studies and 1,718 women, showed an increase in SBP with the use of oral conjugated equine estrogens plus progestogen (SMD = 0.60 mm Hg, 95% CI = 0.19 to 1.01). However, oral or transdermal use of estradiol plus progestogen (SMD = -2.00 mm Hg, 95% CI = -7.26 to 3.27), estradiol alone, and tibolone did not show any significant effect. No significant effect on DBP was observed for any formulation. Women who used oral estrogen plus progestogen had a higher risk of incident hypertension than those who never used it. CONCLUSIONS AND RELEVANCE: The effect of HT on blood pressure is influenced by the formulation used, especially the type of estrogen. The combined formulations of conjugated equine estrogens plus progestogen increased SBP and the risk of hypertension, which was not observed among estradiol plus progestogen, estradiol alone, and tibolone users.

Relugolix/Estradiol/Norethisterone Acetate: A Review in Endometriosis-Associated Pain.

An oral fixed-dose combination of relugolix/estradiol/norethisterone (also known as norethindrone) acetate [Myfembree® (USA); Ryeqo® (EU)] (hereafter referred to as relugolix combination therapy) has been approved in the USA for the management of moderate to severe pain associated with endometriosis in premenopausal women and in the EU for the symptomatic treatment of endometriosis in adult women of reproductive age with a history of previous medical or surgical treatment for their endometriosis. The gonadotropin-releasing hormone (GnRH) receptor antagonist relugolix decreases estradiol and progesterone levels, while the addition of estradiol/norethisterone acetate mitigates hypoestrogenic effects including bone mineral density (BMD) loss and vasomotor symptoms. In two pivotal phase III trials, relugolix combination therapy significantly improved dysmenorrhoea and non-menstrual pelvic pain in premenopausal women with moderate to severe endometriosis. The combination also reduced overall pelvic pain and dyspareunia, reduced analgesic and opioid use, and improved health-related quality of life. The efficacy of relugolix combination therapy was sustained over the longer term (up to 2 years). Relugolix combination therapy was generally well tolerated and BMD loss over time was minimal. With the convenience of a once daily oral dosing regimen, relugolix combination therapy is a valuable addition to the options currently available for the management of endometriosis-associated pain.

Endometriosis is a disease where tissue similar to the lining of the uterus grows outside the uterus and may reach other organs. This causes chronic pain as a result of increased inflammation and scar tissue. Women with endometriosis may experience painful menstrual periods, pelvic pain between periods, pain during sex, painful bowel movements and painful urination. Recently, a fixed-dose tablet comprising relugolix, estradiol and norethisterone (also known as norethindrone) acetate [Myfembree^® (USA); Ryeqo^® (EU)] (hereafter referred to as relugolix combination therapy) has been approved to treat endometriosis-associated pain. The treatment works by decreasing levels of ovarian hormones (estrogen and progesterone). In clinical trials, relugolix combination therapy improved period pain and pain between periods in women with moderate to severe pain associated with endometriosis. The treatment also improved other symptoms (overall pelvic pain and pain during sex), reduced the need for pain medications and improved health-related quality of life. Relugolix combination therapy was generally well tolerated and caused minimal bone loss, which is known to occur with some hormone therapies. With the convenience of a once daily oral pill, relugolix combination therapy is a valuable addition to the options currently available for women with endometriosis-associated pain.

Bioequivalence of Elagolix/Estradiol/Norethindrone Acetate Fixed-Dose Combination Product: Phase 1 Results in Healthy Pre- and Postmenopausal Women.

Fixed-dose combination (FDC) therapies can enhance patient convenience and adherence to prescribed treatment regimens. Elagolix is a novel oral gonadotropin-releasing hormone receptor antagonist approved for management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Hormonal add-back therapy can attenuate the reversible hypoestrogenic effects of elagolix. An FDC formulation containing elagolix/estradiol (E2)/norethindrone acetate (NETA) 300/1/0.5 mg as the morning dose and an elagolix 300 mg capsule as the evening dose, were evaluated in 2 bioequivalence studies including the effects of food. Study 1 in premenopausal women assessed the bioavailability of the elagolix 300-mg capsule relative to the commercially available elagolix 300-mg tablet. Study 2 in postmenopausal women, elagolix/E2/NETA (300 mg/1 mg/0.5 mg) FDC capsule was assessed relative to the elagolix 300-mg tablet coadministered with E2/NETA 1-mg/0.5-mg tablet, the regimen that was studied in Phase 3 uterine fibroid studies. Under fasting conditions, the test elagolix 300-mg capsule was bioequivalent to the reference elagolix 300-mg tablet. Under fasting conditions, the elagolix/E2/NETA FDC capsule was bioequivalent to the coadministered elagolix 300-mg tablet and E2/NETA 1/0.5-mg tablet. Following administration of elagolix/E2/NETA FDC capsule after a high-fat breakfast, elagolix mean maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) were 38% and 28% lower, relative to fasting conditions. NETA mean Cmax was 51% lower and AUC from time 0 to infinity was 20% higher, while baseline-adjusted total estrone mean Cmax and AUC were 46% and 14% lower, respectively. No safety concerns were identified. These results enabled bridging the elagolix/E2/NETA FDC capsule.

Novel Lactation Induction Protocol for a Transgender Woman Wishing to Breastfeed: A Case Report.

Background: Lactation induction in transgender women is a clinical and research priority in the field of breastfeeding medicine. To date, there are four case reports detailing successful induced lactation in transgender patients who wished to breastfeed. The Academy of Breast Feeding Medicine does not formally recommend a specific medication regimen for transgender patients due to lack of high-quality research. Case Presentation: A 50-year-old transgender woman with a hypercoagulable disorder who was able to lactate and breastfeed with novel hormone regimen management at a gender care clinic. Her baseline hormone treatment was an estradiol 0.3 mg transdermal patch every 72 hours and micronized progesterone 200 mg daily. Results: Within four weeks of initiating a modified hormone regimen (estradiol 0.4 mg patch every 72 hours, progesterone 300 mg daily, metoclopramide 10 mg three times daily), the patient was lactating spontaneously. On multiple occasions, she breastfed and expressed up to 30 mL of milk through pumping. Conclusion: This report offers a new effective hormone regimen for transgender patients who wish to lactate and cannot access domperidone-the galactagogue used in previous case reports. It also provides a review of previously published case reports on this subject. Future research in this field should prioritize cohort studies of transgender patients who desire lactation to further assess patient attitudes, experiences, and outcomes.

Assistência ginecológica aos transgênero / Gynecological care for transgenders

Transgênero (trans) é um termo que alberga toda a diversidade de gênero. A incongruência de gênero faz parte desse espectro e refere-se à pessoa cuja identidade de gênero é oposta ao sexo que lhe foi atribuído no nascimento. A terapia hormonal de afirmação de gênero, bem como a cirurgia de afirmação de gênero, é necessária para adequar o corpo ao gênero ao qual a pessoa se identifica. Os homens trans necessitam da terapia com testosterona, que visa reduzir as concentrações de estradiol e incrementar a testosterona circulante para níveis fisiológicos masculinos, resultando em masculinização. A mulher trans receberá o estradiol, associado ou não a um antiandrogênico, visando reduzir a testosterona e incrementar o estrogênio para níveis femininos, resultando em feminização. A cirurgia de afirmação de gênero é, frequentemente, requerida para completar as modificações fenotípicas para o homem e a mulher trans. O ginecologista e obstetra tem um papel crucial no provimento de cuidados a essa população. O presente artigo visa sistematizar algumas ações que o ginecologista e obstetra pode oferecer e que têm potencial para melhorar a qualidade de vida dos homens e mulheres trans. (AU)

Transgenero (trans) is an umbrella term that encompasses all gender diversity. Gender Incongruity is part of this spectrum and refers to the person whose gender identity is opposed to the sex assigned to them at birth. Gender-affirming hormone therapy as well as gender-affirming surgery are necessary to adapt the body to the gender to which the person identifies. Trans men require testosterone therapy to reduce estradiol concentrations and increase circulating testosterone to male physiological levels resulting in masculinization. Trans women will receive estradiol associated or not with an antiandrogenic to reduce testosterone and increase estrogen to female levels resulting in feminization. gender-affirming surgery is often required to complete phenotypic modifications for trans men and women. The gynecologist and obstetrician plays a crucial role in to provide care to this population. This article aims to systematize some actions that the gynecologist and obstetrician can offer to improve the quality of life of trans men and women. (AU)

Efficacy of Alternative Dose Regimens of Exemestane in Postmenopausal Women With Stage 0 to II Estrogen Receptor-Positive Breast Cancer: A Randomized Clinical Trial.

Importance: Successful therapeutic cancer prevention requires definition of the minimal effective dose. Aromatase inhibitors decrease breast cancer incidence in high-risk women, but use in prevention and compliance in adjuvant settings are hampered by adverse events. Objective: To compare the noninferiority percentage change of estradiol in postmenopausal women with estrogen receptor-positive breast cancer given exemestane, 25 mg, 3 times weekly or once weekly vs a standard daily dose with a noninferiority margin of -6%. Design, Setting, and Participants: This multicenter, presurgical, double-blind phase 2b randomized clinical trial evaluated 2 alternative dosing schedules of exemestane. Postmenopausal women with estrogen receptor-positive breast cancer who were candidates for breast surgery were screened from February 1, 2017, to August 31, 2019. Blood samples were collected at baseline and final visit; tissue biomarker changes were assessed from diagnostic biopsy and surgical specimen. Biomarkers were measured in different laboratories between April 2020 and December 2021. Interventions: Exemestane, 25 mg, once daily, 3 times weekly, or once weekly for 4 to 6 weeks before surgery. Main Outcomes and Measures: Serum estradiol concentrations were measured by solid-phase extraction followed by liquid chromatography-tandem mass spectrometry detection. Toxic effects were evaluated using the National Cancer Institute terminology criteria, and Ki-67 was assessed by immunohistochemistry. Results: A total of 180 women were randomized into 1 of the 3 arms; median (IQR) age was 66 (60-71) years, 63 (60-69) years, and 65 (61-70) years in the once-daily, 3-times-weekly, and once-weekly arms, respectively. In the intention-to-treat population (n = 171), the least square mean percentage change of serum estradiol was -89%, -85%, and -60% for exemestane once daily (n = 55), 3 times weekly (n = 56), and once weekly (n = 60), respectively. The difference in estradiol percentage change between the once-daily and 3-times-weekly arms was -3.6% (P for noninferiority = .37), whereas in compliant participants (n = 153), it was 2.0% (97.5% lower confidence limit, -5.6%; P for noninferiority = .02). Among secondary end points, Ki-67 and progesterone receptor were reduced in all arms, with median absolute percentage changes of -7.5%, -5.0%, and -4.0% for Ki-67 in the once-daily, 3-times-weekly, and once-weekly arms, respectively (once daily vs 3 times weekly, P = .31; once daily vs once weekly, P = .06), and -17.0%, -9.0%, and -7.0% for progesterone receptor, respectively. Sex hormone-binding globulin and high-density lipoprotein cholesterol had a better profile among participants in the 3-times-weekly arm compared with once-daily arm. Adverse events were similar in all arms. Conclusions and Relevance: In this randomized clinical trial, exemestane, 25 mg, given 3 times weekly in compliant patients was noninferior to the once-daily dosage in decreasing serum estradiol. This new schedule should be further studied in prevention studies and in women who do not tolerate the daily dose in the adjuvant setting. Trial Registration: ClinicalTrials.gov Identifier: NCT02598557; EudraCT: 2015-005063-16.

The effect of micronized progesterone and medroxyprogesterone acetate in combination with transdermal estradiol on hemostatic biomarkers in postmenopausal women diagnosed with POI and early menopause: a randomized trial.

OBJECTIVE: To compare the impact of micronized progesterone (MP) or medroxyprogesterone acetate (MPA) in combination with transdermal estradiol (t-E2) on traditional coagulation factors and thrombin generation parameters in postmenopausal women diagnosed with premature ovarian insufficiency or early menopause. METHOD: Randomized prospective trial conducted in women diagnosed with premature ovarian insufficiency or early menopause and an intact uterus, recruited over 28 months. All participants were prescribed t-E2 and randomized to either cyclical MP or MPA using a web-based computer randomization software, Graph Pad. Thrombin generation parameters were measured at baseline and repeated after 3-months. Traditional hemostatic biomarkers were measured at baseline and repeated after 3, 6, and 12-months. Seventy-one participants were screened for the study, of whom 66 met the inclusion criteria. In total, 57 participants were randomized: 44 completed the thrombin generation assessment arm of the study, whilst 32 completed 12-months of the traditional coagulation factor screening component of the trial. RESULTS: Thrombin generation parameters did not significantly change from baseline after 3-months duration for either progestogen component when combined with t-E2, unlike the traditional coagulation factors. Protein C activity, free Protein S, and Antithrombin III levels decreased with time in both treatment arms. CONCLUSION: Fluctuations in traditional hemostatic biomarkers were not reproduced by parallel changes in thrombin generation parameters that remained neutral in both groups compared with baseline. The absence of statistically significant changes in thrombin generation for the first 3-months of hormone therapy use is reassuring and would suggest a neutral effect of both progestogens on the global coagulation assay.

Gongning granules plus low dose hormone in pubertal functional uterine hemorrhage: Analysis of hemodynamics and clinical efficacy.

To evaluate the clinical effect of Gongning granules combined with low-dose hormone therapy in pubertal dysfunctional uterine bleeding (PDUB) and its effect on uterine hemodynamics. A total of 164 PDUB patients who were treated in the gynecological outpatient department of our hospital from December 2018 to June 2020 were randomized into study group and control group, with 82 cases each. The control group received estrogen progesterone, and the study group received Gongning granules plus. The clinical efficacy and uterine arterial hemodynamics were compared. The clinical efficacy of the study group was superior to the control group (91.46% vs. 76.83%, P<0.05). The study group yielded shorter bleeding control time and complete hemostasis time than the control group (P<0.05). The amount of menstrual bleeding and duration of menstruation in both groups decreased significantly with time and the study group was significantly lower than the control group (all P<0.05). The endometrial thickness in the study group was significantly thinner than the control group, and the maximum follicle diameter was significantly longer than that in the control group (all P<0.05). After treatment, the platelet count, hemoglobin level of peripheral blood, uterine arterial blood flow and mean flow velocity in the study group were significantly higher than those in the control group (all P<0.05). In addition, there was no significant difference in adverse drug reaction (ADR) between the two groups (P>0.05). In PDUB patients, Gongning granules plus low-dose hormone can significantly relieve bleeding symptoms, improve hemodynamic status and has good safety.

The Influence of Intravaginal Gestagens Treatment on the Morphological Features and Endometrial Steroid Hormone Receptors Content during Anestrus Type II in Dairy Cattle.

BACKGROUND: Gestagens are the most widely used therapy in anestrus type II. The aim of this research is to evaluate the effectiveness of the vaginal progesterone inserts therapy in anestrus type II in cows. METHODS: The study was conducted on 33 cows. Progesterone (PR) and estrogen (ER) receptors expression in endometrium was assessed on a molecular level based on mRNA tissue expression. Additionally, blood 17ß-estradiol and progesterone levels were evaluated. RESULTS: A decrease in mRNA expression of A and B PR and ER α was noted in treated and untreated animals. In the treated group, an increase of ERß mRNA expression was observed, while a decreased was found in untreated animals. There was increased PR, ERα and ß expression in endometrial tissue in treated cows, and decreased expression of these factors in untreated cows. In the treated group, recurrence of ovarian cyclicity was noted in 52% of animals and pregnancy was obtained in 34.8% of them, while in the untreated group, recurrence did not occur. In the control group, spontaneous recurrence of ovarian cyclicity was not observed. An increase of PR expression was correlated with increased proliferation of endometrial cells. CONCLUSIONS: It seems likely that the endometrium is well developed and ready for placentation after removing the exogenous source of progesterone and preventing the recurrence of cyclicity of ovaries.

Influence of Age and Estradiol on Sympathetic Nerve Activity Responses to Exercise in Women.

INTRODUCTION: Postmenopausal women (PMW) display exaggerated increases in blood pressure (BP) during exercise, yet the mechanism(s) involved remain unclear. Moreover, research on the impact of menopausal changes in estradiol on cardiovascular control during exercise are limited. Herein, we tested the hypothesis that sympathetic responses during exercise are augmented in PMWcompared with young women (YW), and estradiol administration attenuates these responses. METHODS: Muscle sympathetic nerve activity (MSNA) and mean arterial pressure (MAP) were measured in 13 PMW (58 ± 1 yr) and 17 YW (22 ± 1 yr) during 2 min of isometric handgrip. Separately, MSNA and BP responses were measured during isometric handgrip in six PMW (53 ± 1 yr) before and after 1 month of transdermal estradiol (100 µg·d-1). A period of postexercise ischemia (PEI) to isolate muscle metaboreflex activation followed all handgrip bouts. RESULTS: Resting MAP was similar between PMW and YW, whereas MSNA was greater in PMW (23 ± 3 vs 8 ± 1 bursts per minute; P < 0.05). During handgrip, the increases in MSNA (PMW Δ16 ± 2 vs YW Δ6 ± 1 bursts per minute; P < 0.05) and MAP (PMW Δ18 ± 2 vs YW Δ12 ± 2 mm Hg; P < 0.05) were greater in PMW and remained augmented during PEI. Estradiol administration decreased resting MAP but not MSNA in PMW. Moreover, MSNA (PMW (-E2) Δ27 ± 8 bursts per minute versus PMW (+E2) Δ12 ± 5 bursts per minute; P < 0.05) and MAP (Δ31 ± 8 mm Hg vs Δ20 ± 6 mm Hg; P < 0.05) responses during handgrip were attenuated in PMW after estradiol administration. Likewise, MAP responses during PEI were lower after estradiol. CONCLUSIONS: These data suggest that PMW exhibit an exaggerated MSNA and BP response to isometric exercise, due in part to heightened metaboreflex activation. Furthermore, estradiol administration attenuated BP and MSNA responses to exercise in PMW.

The Role of Estrone in Feminizing Hormone Treatment.

CONTEXT: In trans women, hormone treatment induces feminization; however, the degree of feminization varies from person to person. A possible contributing factor could be estrone, a weak estrogen that interferes with the estrogen receptor. OBJECTIVE: We assessed whether estrone is involved in feminization induced by hormone treatment. METHODS: This prospective cohort study, with follow-up of 1 year, included 212 adult trans women at a gender identity clinic, who were starting gender-affirming hormone treatment between July 2017 and December 2019, median age 25 years. Change in fat percentage and breast development were assessed. RESULTS: After 12 months of hormone treatment, estrone concentration was 187 pmol/L (95% CI, 153-220) in transdermal and 1516 pmol/L (95% CI, 1284-1748) in oral estradiol users. Fat percentage increased by 1.2% (interquartile range [IQR], 0.3-4.8) in transdermal and 4.6% (IQR, 2.5-5.9) in oral estradiol users. This was not associated with estrone concentrations in transdermal (+4.4% (95% CI, -4.0 to 13) per 100 pmol/L increase in estrone concentration) nor in oral estradiol users (-0.7% [95% CI, -1.7 to 0.3]). Breast volume increased by 69 mL (IQR, 58-134) in transdermal and 62 mL (IQR, 32-95) in oral estradiol users. This was not associated with estrone concentrations in transdermal (+14% [95% CI, -49 to 156] per 100 pmol/L increase in estrone concentration) nor oral estradiol users (+11% [95% CI -14 to 43]). CONCLUSIONS: Change in fat percentage and breast development in trans women were not associated with estrone concentrations nor with administration route. Therefore, measurement of estrone concentrations does not have a place in the monitoring of feminization in trans women.

Vaginal estrogen and association with dementia: A nationwide population-based study.

INTRODUCTION: Use of systemic hormone therapy has been positively associated with development of dementia. Little is known about the dose-dependent effect of vaginal estradiol on dementia risk. METHODS: We assessed associations between cumulative dose of vaginal estradiol tablets and dementia in a case-control study nested in a nationwide Danish cohort of women aged 50 to 60 years at study initiation, who did not use systemic hormone therapy. Each case was age-matched to 10 female controls. RESULTS: A total of 4574 dementia cases were matched to 45,740 controls. Cumulative use of vaginal estradiol tablets was not associated with all-cause dementia; adjusted hazard ratio 1.02 (95% confidence interval [CI] 0.89-1.18) for low dose (< 750 mcg), 1.07 (0.94-1.21) for medium dose (750-2000 mcg), and 0.93 (0.84-1.03) for high dose (> 2000 mcg). Similarly, Alzheimer's disease (AD) only was not associated with vaginal estradiol. DISCUSSION: Exposure to vaginal estradiol tablets was not associated with all-cause dementia or AD only.

Estrogen signaling modulates behavioral selection toward pups and amygdalohippocampal area in the rhomboid nucleus of the bed nucleus of the stria terminalis circuit.

Gonadal steroid hormone influences behavioral choice of adult animals toward pups, parental or aggressive. We previously reported that long-term administration of 17ß-estradiol (E2) to male mice during sexual maturation induces aggressive behavior toward conspecific pups, which is called "infanticide," and significantly enhanced excitatory synaptic transmission in the rhomboid nucleus of bed nucleus of the stria terminalis (BSTrh), which is an important brain region for infanticide. However, it is unclear how estrogen receptor-dependent signaling after sexual maturity regulates neural circuits including the BSTrh. Here we revealed that E2 administration to gonadectomized mice in adulthood elicited infanticidal behavior and enhanced excitatory synaptic transmission in the BSTrh by increasing the probability of glutamate release from the presynaptic terminalis. Next, we performed whole-brain mapping of E2-sensitive brain regions projecting to the BSTrh and found that amygdalohippocampal area (AHi) neurons that project to the BSTrh densely express estrogen receptor 1 (Esr1). Moreover, E2 treatment enhanced synaptic connectivity in the AHi-BSTrh pathway. Together, these results suggest that reinforcement of excitatory inputs from AHi neurons into the BSTrh by estrogen receptor-dependent signaling may contribute to the expression of infanticide.