Pseudopregnant Research Articles

Microscopic Evaluation of Ovarian Surface Epithelium Following Treatment with Conjugated Estrogens in a Mouse Model.

Background:This study was designed to evaluate the effect of different concentrations of conjugated equine estrogens (CEE) on the ovarian epithelium of female CD1 mice. Methods:Twenty-four female mice at 7 months with irregular estrus cycles were randomly divided into four groups of 6 mice each. Group one was considered as a control group and received a daily dose of 0.5ml of propylene glycol, for three weeks, while those in the treatment groups received a daily dose of 14μg/kg, 28μg/kg and 56μg/kg conjugated equine estrogens, respectively. Results:The results from this study showed a strong correlation between elevated concentrations of CEE and histological changes in ovarian surface epithelium (OSE). They also showed that administration of high-dose estrogen created the conditions for excessive proliferation of OSE which may progress into the development of cysts in the ovaries. Conclusion:This study concluded that high concentrations of CEE may increase the chances of developing epithelial ovarian cancer.

028 Fertility and ovarian function in high-dose estrogen-treated tall women

Introduction: High-dose estrogen treatment to reduce final height of tall girls may interfere with normal fertility. We evaluated fertility and ovarian function in tall women who did or did not receive such treatment in adolescence.

Estrogen for the Treatment and Prevention of Breast Cancer: A Tale of 2 Karnofsky Lectures.

In 1971, Sir Alexander Haddow et al. delivered the inaugural David A. Karnofsky lecture at the American Society for Clinical Oncology. This award was designated American Society for Clinical Oncology's highest, as he had used translational research to identify the first clinical therapy, that is, synthetic estrogens to treat breast cancer. His lecture was entitled "Thoughts on Chemical Therapy." For 40 years, high-dose synthetic estrogens were used as palliative therapy, for some advanced breast cancer patients 5 years following menopause. Mechanisms were unknown. Tamoxifen, a failed "morning-after pill," is an antiestrogen in estrogen receptor-positive breast cancer, which was subsequently used to treat all stages of breast cancer and to prevent breast cancer. In 2008, Jordan was selected to present the 38th Karnofsky lecture entitled: "The Paradoxical Action of Estrogen in Breast Cancer-Survival or Death?" Unexpectedly, through a study of acquired resistance to long-term tamoxifen therapy, estrogen-induced apoptosis in long-term estrogen-deprived breast cancer was deciphered in Jordan's laboratory. These data and the biological rules established under laboratory conditions provided molecular mechanisms to aid in the interpretation of the Women's Health initiative in the United States and the Million Women Study in the United Kingdom. In addition, by establishing laboratory models to understand mechanisms of estrogen-induced apoptosis, new estrogen derivatives were successfully evaluated in the laboratory and tested as candidates for women after the therapeutic failure of antiestrogenic strategies to treat breast cancer. For the future, the knowledge obtained about estrogen-induced apoptosis in cancer holds the promise of discovering new therapies to control or cure cancer in general.

Does increasing estrogen dose during frozen embryo transfer affect pregnancy rate?

To assess the effect of increasing estrogen doses during hormone therapy frozen embryo transfer (HT-FET) cycles on endometrial thickness and success rates compared to patients who received fixed estrogen dose. A retrospective study from a university-based fertility clinic during the years 2008-2021. We compared two groups: the fixed-dose group (i.e., received 6mg estradiol dose daily until embryo transfer) and the increased-dose group (i.e., the initial estradiol dose was 6mg daily, and was increased during the cycle). clinical pregnancy rate. The study included 5452 cycles of HT-FET: 4774 cycles in the fixed-dose group and 678 cycles in the increased-dose group. Ultrasound scan on days 2-3 of the cycle showed endometrial thickness slightly different between the two groups (4.2mm in the fixed-dose and 4.0mm in the increased-dose group, P = 0.003). The total estrogen dose was higher, and the treatment duration was longer in the increased than the fixed-dose group (122mg vs. 66mg and 17days vs. 11days, respectively; P < 0.001). The last ultrasound scan done before the addition of progesterone showed that the endometrial thickness was significantly thicker in the fixed than the increased-dose group (9.5mm vs. 8.3mm; P < 0.001). The clinical pregnancy rates were 35.8% in the increased-group vs. 34.1% in the fixed-dose group; P = 0.401. The increased-dose group had thinner endometrium despite the higher doses of estrogen and longer treatment duration than the fixed-dose group. However, the pregnancy rates were similar between the two groups.

Modulation of HIV Replication in Monocyte-Derived Macrophages (MDM) by Host Antiviral Factors Secretory Leukocyte Protease Inhibitor and Serpin Family C Member 1 Induced by Steroid Hormones.

The impact of steroid hormones estrogen and progesterone on human immunodeficiency virus type 1 (HIV-1) replication is well documented. However, the exact mechanism involved in the regulation of HIV-1 replication by estrogen and progesterone is still unclear. In the present study, we wanted to elucidate the molecular mechanisms underlying the modulation of HIV-1 replication by estrogen and progesterone. To achieve this goal, we used real-time quantitative PCR arrays (PCR arrays) to identify differentially expressed host genes in response to hormone treatments that are involved in antiviral responses. Our in vitro results suggest that treatment with high doses of estrogen and progesterone promotes the expression of host antiviral factors Secretory leukocyte protease inhibitor (SLPI) and Serpin family C member 1 (SERPIN C1) among others produced in response to HIV-1 infection. SLPI is an enzyme that inhibits human leukocyte elastase, human cathepsin G, human trypsin, neutrophil elastase, and mast cell chymase. SERPIN C1 is a plasma protease inhibitor that regulates the blood coagulation cascade by the inhibition of thrombin and other activated serine proteases of the coagulation system. A dose dependent downmodulation of HIV-1 replication was observed in monocyte-derived macrophages (MDMs) pre-treated with the two proteins SLPI and SERPIN C1. Further investigations suggests that the host antiviral factors, SLPI and SERPIN C1 act at the pre-integration stage, inhibiting HIV-1 viral entry and leading to the observed downmodulation of HIV-1 replication. Our studies would help identify molecular mechanisms and pathways involved in HIV-1 pathogenesis.

Association of pregnancy with engagement in HIV care among women with HIV in the UK: a cohort study.

Women with HIV face challenges in engaging in HIV care post partum. We aimed to examine changes in engagement in HIV care through clinic attendance before, during, and after pregnancy, compared with matched women with HIV who had never had a recorded pregnancy. In this cohort study, we describe changes in engagement in HIV care before, during, and after pregnancy among women with HIV from the UK Collaborative HIV Cohort (CHIC) study from 25 HIV clinics in the UK with a livebirth reported to the National Surveillance of HIV in Pregnancy and Childhood between Jan 1, 2000, and Dec 31, 2017. To investigate whether changes were specific to HIV, we compared these changes to those over equivalent periods among non-pregnant women with HIV in the UK CHIC study matched for ethnicity, year of conception, age, CD4 cell count, viral suppression, and antiretroviral therapy use. Analyses were via logistic regression using generalised estimated equations with an interaction between case-control status (pregnant women vs non-pregnant women) and pregnancy or pseudo pregnancy (for non-pregnant women) stage. 1116 matched pairs of pregnant and non-pregnant women were included (median age 34 years [IQR 30-38], 80·1% Black African, 12·5% white). 69 330 person-months of follow-up were recorded, 25 412 in the before stage, 18 897 during, and 25 021 after pregnancy or pseudo pregnancy stages. Among pregnant women, the proportion of time engaged in care increased during pregnancy (8477 [90·5%] of 9371 person-months) and after pregnancy (10 501 [84·6%] of 12 407), compared with before pregnancy (9979 [78·5%] of 12 707). Among non-pregnant women in the control group, engagement in HIV care remained stable across the three equivalent stages (9688 [76·3%] of 12 705 person-months before pseudo pregnancy; 7463 [78·3%] of 9526 during pseudo pregnancy; and 9892 [78·4%] of 12 614 after pseudo pregnancy). The association of engagement in HIV care with pregnancy or pseudo pregnancy stage differed significantly by case-control status (pinteraction<0·0001); the odds of engagement in HIV care were higher during pregnancy (odds ratio [OR] 3·32, 95% CI 2·68-4·12) and after pregnancy (OR 1·49, 1·24-1·79) only among pregnant women, and not among non-pregnant women, when compared with the before pseudo pregnancy stage. Women with HIV and a pregnancy resulting in a livebirth were more likely to engage in HIV care post partum when compared with before pregnancy. A detailed understanding of the reason for this finding could support interventions to maximise engagement in HIV care for all women with HIV. Medical Research Council and National Institute for Health Research.

Impact of frozen thawed embryo transfer in hormone substituted cycles on thrombotic risk markers

IntroductionFertility treatment with frozen thawed embryo transfer (FET) is widely used. Women treated in artificial cycles (AC-FET) receive high doses of estrogen in contrast to natural cycles (NC-FET), where no estrogen is administered. Estrogen substitution may be associated with increased risk of thromboembolism. Our aim is therefore to characterize changes in blood coagulation parameters defined as surrogate thrombotic risk markers in women undergoing estrogen substitution during AC-FET. MaterialsIn our prospective cohort study, we enrolled 34 women in either: AC-FET (n = 19) or NC-FET (n = 15). Women were recruited at the Department of Obstetrics and Gynaecology, Horsens Fertility Clinic, Denmark, from August 2019 – November 2020. Blood samples were obtained at four timepoints. Thrombin generation, platelet aggregation and fibrinolysis were evaluated as thrombotic risk markers. ResultsWithin the AC-FET group, we found a significantly shorter lagtime (p < 0.05) and time to peak (TTP) (p < 0.001) after hormone substitution compared to baseline. Furthermore, a significantly higher mean peak (p < 0.0001) and larger endogenous thrombin potential (ETP) (p < 0.0001) was observed. When compared to the NC-FET group, women receiving AC-FET had a significantly shorter mean TTP (p < 0.005), higher mean peak (p < 0.0001) and larger ETP (p < 0.05). Additionally, we demonstrated a significantly prolonged lysis time within the AC-FET group (p < 0.001). ConclusionOur results indicate that women receiving AC-FET have a significantly increased thrombin generation which may increase the thromboembolic risk in women being estrogen substituted.

A high dose of estrogen can improve renal ischemia-reperfusion-induced pulmonary injury in ovariectomized female rats.

Renal ischemia-reperfusion injury (RIRI) as a pathological process induces remote organ injury such as lung complications and it is regulated in a hormone-dependent manner. This study investigates the effect of estrogen on RIR-induced pulmonary injury in ovariectomized (OV) rats. A total of 60 female Wistar rats were divided into six groups: (i) intact sham, (ii) OV sham, (iii) OV sham + estradiol valerate (E), (iv) intact ischemia, (v) OV ischemia, and (vi) OV ischemia + E. Bilateral ischemia was performed for 45min in all groups except sham. Before the ischemia, OV groups received an intramuscular (i.m.) injection of E. After reperfusion, blood samples were collected for serum analysis and kidney and lung tissue were separated for pathological experiment and malondialdehyde (MDA) and nitrite measurement. The left lung was weighed to measure pulmonary edema. Estrogen deficiency caused a greater increase in blood urea nitrogen and creatinine levels during IRI. Ischemia reduced nitrite of serum and lung tissue. The increased level of MDA during ischemia, returned to normal levels via estrogen injection. The severity of renal and lung damage in ischemic groups increased significantly, and estrogen improved this injury. Estrogen as an antioxidant agent can reduce oxidative stress and may improve renal function and ameliorating lung damage caused by RIR.

Mouldy Matriarchs and Dangerous Daughters

Mouldy Matriarchs and Dangerous Daughters

O-182 Higher risk of preeclampsia and pregnancy-induced hypertension with artificial cycle for Frozen-thawed Embryo Transfer compared to ovulatory cycle or fresh transfer following In Vitro Fertilization

Abstract Study question Is there an increased risk of preeclampsia after Frozen-thawed Embryo Transfer(FET) compared to In Vitro Fertilization-fresh transfer(IVF-fresh-ET) according to endometrial type of preparation for FET? Summary answer The frequency of preeclampsia and hypertension were significantly higher in the group of artificial cycle (AC-FET) compared to ovulatory cycle (OC-FET) and fresh-ET (P &amp;lt; 0.0001). What is known already Risks of maternal morbidity are known to be reduced in pregnancies resulting from FET compared to fresh-ET except for the risk of preeclampsia, that was reported to be significantly higher in pregnancies resulting from FET compared to fresh-ET or spontaneous conception. Most recent studies demonstrate an equal live birth rate with either OC-FET or AC-FET preparation. Few studies compared the maternal vascular morbidities with the two hormonal environments that preside over the early stages of embryonic development: OC (major role of the corpus luteum) and AC (prolonged hormone replacement with high doses of estrogen and progesterone). Study design, size, duration We conducted a 2013-2018 French nationwide cohort study comparing maternal vascular morbidities in 3 groups of single pregnancies&amp;gt; 22 weeks of gestation (WG): FET with AC or OC preparation, and IVF (conventional or ICSI)-fresh-ET.Data were extracted from the French National Health System database (&amp;gt;99% of national deliveries) in which all hospitalizations are registered, containing information on patient characteristics, diagnoses and treatments. Records were merged anonymously. Access to the database was legally approved. Participants/materials, setting, methods 68 025 deliveries were included: fresh-ET(n = 48 152), OC-FET(n = 9 500), AC-FET(n = 10 373). In OC-FET, a luteal phase support with progesterone was administered for maximum 6 WG if pregnancy. In AC-FET, progesterone was co-administered with estrogen until 12 WG. Embryos were transferred at cleavage or blastocyst stage. Vascular disorders were recorded if hospitalization for preeclampsia/eclampsia or hypertension (history of hypertension excluded). Maternal characteristics were included in multivariate analysis. Adjusted odds ratios(aOR) and 95% confidence intervals(CI) were estimated. Main results and the role of chance Maternal characteristics: In multivariate analysis, patients in the FET groups were older (33.4 years (std=4.3) vs. 33.2 years (std=4.4) for fresh-ET, respectively, P &amp;lt; 0.0001), less often primiparous (aOR=0.68[0.66-0.71], P &amp;lt; 0.0001) or smokers (aOR=0.84[0.75-0.95]) or with premature ovarian insufficiency (POI) (aOR=0.68 [0.58-0.79]), more frequently with polycystic ovaries (PCOS) (aOR=1.25[1.12-1.39]) and comparable for obesity or diabetes. In FET groups, 52.2% were AC-FET. There was no difference for maternal age, parity, obesity, smoking, history of diabetes between AC and OC-FET. Endometriosis (aOR=1.26[1.16-1.38]), PCOS (aOR=1.79[1.50-2.15]) and POI (aOR=2.0[1.48-2.72]) were more frequent in AC-FET. Risks of vascular disorders The rate of preeclampsia (5.3% vs. 2.3% vs. 2.4%, respectively, P &amp;lt; 0.0001) and hypertension (4.7% vs. 3.4% vs. 3.3%, respectively, P = 0.0002) was significantly higher in AC-FET versus OC-FET and fresh-ET. In multivariate analysis, the risk of preeclampsia increased with age, primiparity, obesity, diabetes and POI. The risk was higher in AC-FET versus OC-FET (aOR=2.42 [2.06-2.85]) and fresh-ET (aOR=2.43[2.2-2.7]), P &amp;lt; 0.00001. No difference was found between OC-FET and fresh-ET (P = 0.91). The risk of pregnancy-induced hypertension increased with age &amp;gt;40, primiparity, smoking, obesity and diabetes and was higher in AC-FET versus OC-FET (aOR=1.50[1.29-1.74], P &amp;lt; 0.0001) and fresh-ET (aOR=1.50[1.35-1.67], P &amp;lt; 0.0001) and not different between OC-FET and fresh-ET (P = 0.86). Limitations, reasons for caution While the strength of this study relies in the number and exhaustiveness of subjects analysed, its limitations are its retrospective and register-based nature that did not enable to refine the risk according to details of techniques and treatments in each group. Wider implications of the findings This large nationwide cohort study highlights 2 important information for physicians : i) the possible deleterious role of high supra-physiological and prolonged doses of estrogen-progesterone supplementation on vascular pathologies ii) the protective role of the corpus luteum present in stimulated or spontaneous OC for their prevention. Trial registration number Not applicable

Carbamazepine protects the endometrium against negative effects of estrogen in rats

ABSTRACT Carbamazepine (CMZ) increases estrogen metabolism by inducing cytochrome P450 (CYP3A4). We investigated whether CMZ is protective against endometrial hyperplasia (EH). We used 32 female Wistar albino rats divided into four equal groups: the control group received drinking water, the estradiol valerate (EV) group was given EV, the CMZ group was given CMZ, and the EV + CMZ group was given both EV and CMZ. After 30 days the uteri of the rats were removed and serum estrogen and progesterone levels were measured, and endometrial tissue characteristics were evaluated. CYP3A4 expression was assessed using immunohistochemistry. Serum estrogen levels were lowest in the EV group and highest in the CMZ group. Serum progesterone levels were similar among all groups. Glandular density, a proxy measure of EH, was highest in the EV group and lowest in the EV + CMZ group. EH was detected in six of eight rats (75%) in the EV group and two of eight rats (25%) in the EV + CMZ group. Immunohistochemical staining revealed no significant difference in CYP3A4 expression among the four groups. CMZ reduced the negative effect of high dose estrogen that is not balanced by progesterone on the endometrium in rats. The effect likely is probably due to the CYP3A4 enzyme activator effect. CMZ may be protective against EH in high risk women, although confirmation is required.

Assessment of Estradiol-Induced Gonadotropin Surge Generation: Preliminary Results From a Protocol of Graded Transdermal Estradiol Dosing

In normally-cycling women, high midcycle estradiol (E2) concentrations (> 200-300 pg/ml) derived from the dominant follicle trigger an approximately 10-fold increase in LH and 4-fold increase in FSH levels—the gonadotropin surge—over about 48 hours. In prenatally-androgenized female rats and sheep (animal models with polycystic ovary syndrome [PCOS]-like features), high-dose estrogen fails to initiate gonadotropin surges. However, it remains unclear whether E2-induced gonadotropin surge generation is defective in PCOS. Baird et al., induced LH surges in 12 women with PCOS and 6 normally-cycling controls (studied in the early follicular phase) with 3 days of high-dose oral ethinyl E2, and the LH peak magnitude was similar in both groups (JCEM 1977;45:798-801). However, the dose of ethinyl E2 in this study (200 mcg/day) was markedly supraphysiological, and the dosing schedule did not mimic the normal, gradual increase in E2 levels observed in normal follicular phases. To further assess potential impairments in E2 augmentation of gonadotropin secretion in PCOS, we developed a study protocol involving graded transdermal E2 dosing (with dose adjustments as needed) to gradually achieve serum E2 concentrations approximating 300-400 pg/ml. Herein we present our early experience with this protocol in six normally-cycling, non-hyperandrogenic women: median (range) age 23.1 (19.8–29.0) years, body mass index 20.7 (19.2–27.2) kg/m2, calculated serum free testosterone 2.7 (2.4–5.3) pg/ml. Study subjects began transdermal E2 on cycle day 4 with the following dose-escalation protocol: 0.2 mg/d x 1 day, then 0.3 mg/d x 1 day, then 0.4 mg/d x 1 day, then 0.5 mg/d. Daily serum E2 measurements informed dose adjustments (e.g., a measured E2 level > 400 pg/ml prompted a dose reduction; a measured E2 level < 250 pg/ml while on the 0.5 mg/d dose prompted a dose increase to 0.6 mg/d). In these six women, daily E2 values (pg/ml) were as follows: baseline 31 (17–36) (median [IQR]) on cycle day 4 (the morning of E2 initiation); 205 (135–240) on day 5; 159 (135–270) on day 6; 263 (202–363) on day 7; 276 (239–351) on day 8; 328 (307–367) on day 9; 333 (269–402) on day 10; and 328 (253–354) on day 11. Median transdermal E2 doses (mg/d) on days 5 through 11 were 0.2, 0.3, 0.4, 0.35, 0.4, 0.4, and 0.4, respectively. Morning serum LH concentrations (median [IQR]) were 5.2 (3.5–6.1) IU/L immediately before E2 initiation (cycle day 4), decreased to a nadir of 1.5 (1.0–2.4) IU/L after 2 days of E2 (cycle day 6), thereafter increasing 8.1-fold to a peak of 12.1 (8.1–18.3) IU/L after 5 days of E2 (cycle day 9). FSH similarly changed from baseline median 3.5 (3.4–4.2) IU/L to nadir median of 1.6 (1.2–1.8) IU/L after 2 days of E2, thereafter increasing again to 3.5 (2.6–4.0) IU/L after 5 days of E2. We conclude that this experimental protocol may be useful to investigate potential defects in E2-induced LH surge generation in PCOS.

New trends in current menopausal hormone therapy

The article presents the results of recent studies on the effectiveness, safety and duration of menopausal hormone therapy (MHT). The main cardio-metabolic risk factors for cardiovascular diseases are formed in women precisely during the transition to menopause and are clearly associated with the appearance of vegetative menopausal symptoms and the development of endothelial dysfunction, which is a predictor of future serious health problems, especially cardiovascular diseases. The results of a number of epidemiological studies have shown that in women with severe climacteric manifestations, especially with hot flashes, the overall risk of developing cardiovascular diseases is increased. The need for early initiation of MHT is an indisputable truth and is not disputed by anyone, but the formed tendency to discontinue treatment in 56 years raises many questions among patients and their doctors. However, recent guidelines from the International Menopause Society state that there is no reason to arbitrarily limit the duration of MHT. This paper presents current evidence on the indications and benefits of low and ultra-low doses of MHT. In view of the high efficacy and safety of low doses of MHT, they seem to be the most acceptable starting doses of oral MHT for most women. In addition, women with early menopause should also receive higher doses of estrogens, as they are more physiological for them. The choice in favor of starting MHT in a postmenopausal woman with a low or ultra-low dose in each case should be selected individually.

Oral contraceptive use by formulation and endometrial cancer risk among women born in 1947\u20131964: The Nurses\u2019 Health Study II, a prospective cohort study

Oral contraceptives (OCs) have been associated with long-term lower endometrial cancer risk; relatively little is known about associations with more recent OC formulations and associations with longer-term risk. A total of 107,069 women from the Nurses’ Health Study II recalled OC use from age 13 to baseline (1989); biennial questionnaires updated data on OC use until 2009. OCs were classified by estrogen and progestin type, dose, and potency based on reported brand. 864 incident endometrial cancer cases were identified through 2017. Multivariable Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals [95% CI] for the association of OC use with endometrial cancer risk. OC use was associated with lower endometrial cancer risk (ever use, HR 0.77 [95% CI 0.65–0.91]; >10 years of use, 0.43 [0.32–0.58] vs. never OC use). Inverse associations for duration were evident regardless of time since last use. Longer durations (> 5 years) of ethinyl estradiol (0.52 [0.41–0.67]) and second-generation progestins (0.43 [0.30–0.61]), both versus never use, were more strongly associated with lower risk than mestranol (0.66 [0.50–0.88], p-het = 0.01) and first-generation progestins (0.62 [0.49–0.78], p-het = 0.03). Inverse associations were generally observed for cross-classified cumulative average estrogen and progestin dose and potency (< vs. ≥ median; ever use vs. never OC use), with the exception of high estrogen and low progestin dose. OCs were associated with lower endometrial cancer risk, independent of time since last use. Use of ethinyl estradiol and second-generation progestins were more strongly inversely associated with risk compared with older formulations.

PRP-THERAPY OF ENDOMETRIUM: THE LATEST METHODS IN THE FIELD OF ASSISTED REPRODUCTIVE TECHNOLOGIES

Recently, the preparation of the endometrium for embryo transfer, namely the achievement of optimal thickness and receptivity of the endometrium, the prevention of unsuccessful attempts to implant embryos, is gaining more and more attention among doctors in the field of reproductive medicine. Since cryptocycles of embryo transfer preparation are often discontinued in the practice of a reproductive physician due to insufficient endometrial thickness, high doses of estrogen and negative IVF results provided the satisfactory condition of the endometrium on the day of transfer and quality of the embryos. The article briefly presents the views on the effectiveness of PRP therapy of the endometrium in the protocols of preparation for embryo transfer. The main mechanisms of the effect of platelet-rich blood plasma on the endometrium are elucidated. The positive effect of this technique on regeneration, increase in thickness and improvement of endometrial receptivity is proved.&#x0D; Conclusion. PRP-therapy of the endometrium is a modern, affordable, effective and safe method of treatment of thin and damaged endometrium in reproductive medicine.

50th anniversary of the first clinical trial with ICI 46,474 (tamoxifen): then what happened?

Following the discovery and approval of the oral contraceptive, the pharmaceutical industry sought new opportunities for the regulation of reproduction. The discovery of the first non-steroidal anti-oestrogen MER25, with antifertility properties in laboratory animals, started a search for 'morning-after pills'. There were multiple options in the 1960s, however, one compound ICI 46,474 was investigated, but found to induce ovulation in subfertile women. A second option was to treat stage IV breast cancer. Although the patent for ICI 46,474 was awarded in the early 1960s in the UK and around the world, a patent in the USA was denied on the basis that the claims for breast cancer treatment were not supported by evidence. A trial at the Christie Hospital and Holt Radium Institute in Manchester, published in 1971, showed activity compared with alternatives: high-dose oestrogen or androgen treatment, but the US Patent Office was unswayed until 1985! The future of tamoxifen to be, was in the balance in 1972 but the project went forward as an orphan drug looking for applications and a translational research strategy was needed. Today, tamoxifen is known as the first targeted therapy in cancer with successful applications to treat all stages of breast cancer, male breast cancer, and the first medicine for the reduction of breast cancer incidence in high-risk pre- and post-menopausal women. This is the unlikely story of how an orphan medicine changed medical practice around the world, with millions of women's lives extended.

S2417 The Skinny on Estrogen and Liver Fat

INTRODUCTION: Hepatic steatosis is a common condition defined as fat comprising >5% of liver sample without evidence of inflammation. We present a case of a 23 year old transgender female who presented with an abrupt rise in liver enzymes after 18 months of hormone therapy found to have significant steatosis on biopsy. CASE DESCRIPTION/METHODS: There was evidence of mildly elevated liver enzymes prior to starting estrogen therapy for transition with low normal BMI and enzymes were monitored closely while on estrogen. A complete serologic evaluation was done without evidence of alternate cause for rise in enzymes and biopsy revealed 40% steatosis without hepatocyte ballooning, necroinflammation or fibrosis. The patient had no medical history and denied medications or supplement use aside from those used for gender affirmation. There was no history of obesity, rapid weight gain or metabolic conditions. Her BMI was 23 and she had been on a stable dose of estrogen (with sub-therapeutic estrogen levels) for 18 months. DISCUSSION: This case represents a unique presentation of hepatic steatosis in the transgender population. The majority of what is known regarding liver toxicity of estrogen is derived from the study of hormone replacement therapy and oral contraceptive use and these are not identical to the regimens used for transition. Oral contraceptives usually include estrogen and progesterone and hormone replacement regimens use lower doses than in gender affirmation. Liver disease related to estrogen use varies widely depending on dose and formulation, but has not been studied in the transgender population using estrogen for gender affirmation. Tamoxifen, a selective estrogen receptor modulator, widely used in breast cancer therapy has been shown to have estrogenic effects on the liver, bone, and brain. Up to a third of tamoxifen patients develop steatosis independent of weight gain. It generally develops in the first 2 years of therapy and may progress to cirrhosis in as few as 3 years. The use of high dose estrogen therapy in gender affirmation may more closely mimic the mechanism of effect on liver tissue of tamoxifen rather than the direct correlate of hormone replacement as the doses are significantly lower and not adjusted based on serum levels in post-menopausal women. This case highlights the need for further study into estrogenic effects on the liver tissue and optimal screening and evaluation for transgender women who require high dose estrogen supplementation lifelong.

Worsening pulmonary outcomes during sex reassignment therapy in a transgender female with cystic fibrosis (CF) and asthma/allergic bronchopulmonary aspergillosis: a case report

BackgroundCystic Fibrosis (CF) is a hereditary pulmonary and extra-pulmonary disease that occurs equally in men and women. However, a difference in morbidity and mortality rates between the sexes has been long documented. Similarly, a sex-disparity in disease severity has been reported in asthma as well. Studies done to date point to estrogen as a possible cause of this sex disparity in pulmonary outcomes in both conditions.Case presentationHere, we describe a case of a patient with CF and asthma/allergic bronchopulmonary aspergillosis (ABPA) undergoing sex reassignment therapy (male-to-female) and the negative impact it had on her lung function and frequency of pulmonary exacerbations in the context of increasing doses of exogenous estrogen.ConclusionsThis case raises the possibility of a link between estrogen and worsening pulmonary outcomes and the need for further studies into transgender individuals with CF and/or asthma/ABPA as well as those undergoing high dose estrogen therapy for other indications.

Different regrouping schedules in semi group-housed rabbit does: Effects on agonistic behaviour, stress and lesions

Although group housing of naturally social animals like rabbits (Oryctolagus cuniculus) is desirable for ethical reasons, social conflicts can significantly increase the risk for injuries as well as stress incidences and negatively affect their welfare. A common housing system in Switzerland is the "semi group-housing". Here, rabbit does are kept individually shortly before the birth of their kits until 12 days post-partum (pp) after which they are regrouped. Despite positive aspects of this housing system, like the reduction of pseudo pregnancy and crushing of kits, fights between the does often occur after the regrouping process. This study examined whether prolonged postpartum separation may reduce agonistic interactions, stress, and lesions. In total, data were collected over 5 trials on 57 Hycole breeding does. Per trial, three groups of 8 does each were artificially inseminated on day 10 pp and regrouped on either day 12, 18 or 22 pp. Non-pregnant does were replaced in every trial. Agonistic behaviour, anogenital distance, lesions and increased body temperature, as a stress indicator, were documented. The effect of the regrouping treatment on the rate of injury and agonistic interactions was different depending on the trial (lesions: interaction trial x treatment χ2 = 44.21, df = 8, P < 0.0001; agonistic interactions: interaction treatment x trial χ2 = 23.59, df = 8, P = 0.003). During winter trials (November- February), the numbers of lesions and agonistic interactions were generally lower than in the trials during summer. None of the animals with temperature transponders showed a body temperature increase after regrouping (P = 0.98), however, there was an increase after the artificial insemination (P = 0.019). The anogenital distance, measured during the artificial insemination process, was not correlated to the aggressive behaviour of does (r = 0.028; P = 0.78). These findings suggest that prolonging single housing only reduced lesions and fighting in some trials but failed to do so in others. Group composition, individuality and season are discussed as relevant factors for the extent of agonistic interactions. Against our expectations, in none of the groups a stress response after regrouping was found according to body temperature measures.

Energy homeostasis in rabbit does during pregnancy and pseudopregnancy

This study was conducted to evaluate the changing concentrations of metabolic hormones and metabolites in pregnant (P) and pseudopregnant (PP) rabbit does. Twenty-five New Zealand White rabbit does were submitted to artificial insemination (AI) and then classified as P (n = 15) or PP (n = 10). Blood samples were collected weekly until day 32 post AI. During pregnancy, leptin concentrations were greater on Days 14 and 21 (P < 0.05), while insulin was greater on days 21 and 32 post AI (P < 0.05) compared to PP does. The triiodothyronine/thyroxine (T3/T4) ratio was greater in the first and last week (P < 0.001); whereas, cortisol concentrations were greater in the last week of pregnancy and after parturition (P < 0.01) compared with that of PP does. Non-esterified fatty acids (NEFA) concentrations increased from day 7 until day 32 post AI (P < 0.05). Glucose concentrations were unchanged throughout pregnancy although concentrations were positively associated with litter size. These results indicate concentrations of hormones and metabolites change during pregnancy to ensure energy requirements are met for both the foetuses and the maternal tissues. Physiological hyperleptinemia, hyperinsulinemia, and changes in cortisol as well as thyroid hormones indicate there is an adaptation of metabolic functions induced by pregnancy. These adaptations could be mediated by gonadal steroids because changes mainly occur in the second half of pregnancy when the profile of the sex hormones differs between P and PP does.