Mechanisms of Scarless Repair at Time of Menstruation: Insights From Mouse Models

The human endometrium is a remarkable tissue which may experience up to 400 cycles of hormone-driven proliferation, differentiation and breakdown during a woman's reproductive lifetime. During menstruation, when the luminal portion of tissue breaks down, it resembles a bloody wound with piecemeal shedding, exposure of underlying stroma and a strong inflammatory reaction. In the absence of pathology within a few days the integrity of the tissue is restored without formation of a scar and the endometrium is able to respond appropriately to subsequent endocrine signals in preparation for establishment of pregnancy if fertilization occurs. Understanding mechanisms regulating scarless repair of the endometrium is important both for design of therapies which can treat conditions where this is aberrant (heavy menstrual bleeding, fibroids, endometriosis, Asherman's syndrome) as well as to provide new information that might allow us to reduce fibrosis and scar formation in other tissues. Menstruation only occurs naturally in species that exhibit spontaneous stromal cell decidualization during the fertile cycle such as primates (including women) and the Spiny mouse. To take advantage of genetic models and detailed time course analysis, mouse models of endometrial shedding/repair involving hormonal manipulation, artificial induction of decidualization and hormone withdrawal have been developed and refined. These models are useful in modeling dynamic changes across the time course of repair and have recapitulated key features of endometrial repair in women including local hypoxia and immune cell recruitment. In this review we will consider the evidence that scarless repair of endometrial tissue involves changes in stromal cell function including mesenchyme to epithelial transition, epithelial cell proliferation and multiple populations of immune cells. Processes contributing to endometrial fibrosis (Asherman's syndrome) as well as scarless repair of other tissues including skin and oral mucosa are compared to that of menstrual repair.

Immunoreactivity of the SARS-CoV-2 entry proteins ACE-2 and TMPRSS-2 in murine models of hormonal manipulation, ageing, and cardiac injury

Previous work indicates that SARS-CoV-2 virus entry proteins angiotensin-converting enzyme 2 (ACE-2) and the cell surface transmembrane protease serine 2 (TMPRSS-2) are regulated by sex hormones. However, clinical studies addressing this association have yielded conflicting results. We sought to analyze the impact of sex hormones, age, and cardiovascular disease on ACE-2 and TMPRSS-2 expression in different mouse models. ACE-2 and TMPRSS-2 expression was analyzed by immunostaining in a variety of tissues obtained from FVB/N mice undergoing either gonadectomy or sham-surgery and being subjected to ischemia–reperfusion injury or transverse aortic constriction surgery. In lung tissues sex did not have a significant impact on the expression of ACE-2 and TMPRSS-2. On the contrary, following myocardial injury, female sex was associated to a lower expression of ACE-2 at the level of the kidney tubules. In addition, after myocardial injury, a significant correlation between younger age and higher expression of both ACE-2 and TMPRSS-2 was observed for lung alveoli and bronchioli, kidney tubules, and liver sinusoids. Our experimental data indicate that gonadal hormones and biological sex do not alter ACE-2 and TMPRSS-2 expression in the respiratory tract in mice, independent of disease state. Thus, sex differences in ACE-2 and TMPRSS-2 protein expression observed in mice may not explain the higher disease burden of COVID-19 among men.

Translational Applications of Linear and Circular Long Noncoding RNAs in Endometriosis

Endometriosis is a chronic gynecologic disease that negatively affects the quality of life of many women. Unfortunately, endometriosis does not have a cure. The current medical treatments involve hormonal manipulation with unwanted side effects and high recurrence rates after stopping the medication. Sadly, a definitive diagnosis for endometriosis requires invasive surgical procedures, with the risk of complications, additional surgeries in the future, and a high rate of recurrence. Both improved therapies and noninvasive diagnostic tests are needed. The unique molecular features of endometriosis have been studied at the coding gene level. While the molecular components of endometriosis at the small RNA level have been studied extensively, other noncoding RNAs, such as long intergenic noncoding RNAs and the more recently discovered subset of long noncoding RNAs called circular RNAs, have been studied more limitedly. This review describes the molecular formation of long noncoding and the unique circumstances of the formation of circular long noncoding RNAs, their expression and function in endometriosis, and promising preclinical studies. Continued translational research on long noncoding RNAs, including the more stable circular long noncoding RNAs, may lead to improved therapeutic and diagnostic opportunities.

The Evidence for Fertility Preservation in Pediatric Klinefelter Syndrome

Klinefelter syndrome (KS) is a common cause of non-obstructive azoospermia (NOA). Advances in fertility preservation (FP) techniques, such as the use of microdissection testicular sperm extraction (micro-TESE), have improved sperm retrieval rates (SRR) up to 40–50% in this population. Age has been suggested to have an impact on FP, postulating that sperm production may deteriorate over time due to germ cell loss. As such, sperm retrieval for patients with KS at a younger age has been proposed to further improve SRR; however, whether such practice pragmatically improves SRR is yet to be determined, and controversy remains with concerns over trauma caused by FP procedures on further impairment of testicular function. There has also been a debate on the ethics of performing FP procedures in the pediatric population. Optimizing FP for patients with KS invariably requires a holistic multidisciplinary approach. This review aimed to evaluate the latest evidence in performing FP in pediatric patients with KS, and discuss the controversy surrounding such practice. Hormonal changes in patients with KS during childhood and the use of hormonal manipulation to optimize SSR in this population have also been reviewed.

A sex chromosome drives the emergence of vocal learning following hormonal manipulation in female zebra finches

Zebra finches are sexually dimorphic vocal learners. Males learn to sing by imitating mature conspecifics, but females do not. The lack of vocal learning in females is associated with anatomical differences in the neural circuits responsible for vocal learning, including the atrophy of several brain regions during development. However, this atrophy can be prevented and song learning retained in females after pharmacological estrogen treatment. Little is known about the genetic machinery controlling this sex and estrogen responsive song system development. To screen for drivers, we performed an unbiased analysis of transcriptomes from song control nuclei and surrounding motor regions in zebra finches of either sex treated with 17-B-estradiol or vehicle until sacrifice on day 30, when divergence between the sexes is anatomically apparent. Utilizing the newly assembled autosomes and sex chromosomes from the zebra finch Vertebrate Genomes Project assemblies, we identified correlated gene modules that were associated to song nuclei in a sex and estradiol dependent manner. Female estradiol treated HVC, in the vocal learning circuit, acquired the smallest of the modular specializations observed in male HVC. This module was enriched for genes governing anatomical development, and its specilization was dispraportionately influenced by the expression of Z sex chromosome transcripts in HVC. We propose that vocal learning may be prevented in female zebra finches via the suppression of an estrogen inducible Z chromosome cis-acting regulatory element.

Evaluating the role of aromatase inhibitors (AIs) in the treatment of endometrial stromal sarcomas (ESS).

5575 Background: Endometrial stromal sarcomas (ESS) account for < 20% of uterine sarcomas. They usually express estrogen and progesterone receptors (ER/PR) and are considered hormone sensitive. Due to the rarity of these tumors, large clinical trials studying optimal treatment have not been possible. This study represents the largest retrospective study of ESS treated with AI. Methods: The clinicopathological variables and outcomes of patients (pts) with pathologically confirmed low grade ESS treated with AI at our institution between 1998-2020 were recorded. Results: 48 pts with ESS treated with AI were identified. They had a median age of 54 years (range 23-84) and BMI of 27 (range 20-50). 79% were white. 6 (12%), 9 (19%), 14 (29%) and 19 pts (40%) had stage 1,2,3,4 ESS, respectively. 37 (77%) were ER+/PR+; 2 (4%) ER+/PR- and 9 pts (19%) had unknown ER/PR status. All pts were postmenopausal at AI initiation. 12 pts (25%) had a synchronous cancer (5 of these had breast cancer {3 of the 5 presented post tamoxifen}). 23 pts (48%) received megestrol acetate and 25 (52%) an AI as first line hormonal manipulation. During their disease course, 35 pts (73%) received letrozole, 21 (44%) anastrozole and 19 (39.6%) exemestane. 22 pts (46%) were treated with more than one AI. 28 pts (58%) reported side-effects; arthralgia (33%) being the most common. 10 pts (21%) discontinued AI due to toxicity; 12 pts (25%) switched AI for toxicity (with improved tolerance in 67% of these pts). Among the 24 pts (50%) with measurable disease there were 2 partial responses (objective response rate of 8.3%). 1-year disease control rate (DCR) was (79%) for all pts and 58% in stage 4 disease. Median PFS for 1st line AI was 161.6 months (95% CI 48.5 to 274.7). Conclusions: This study represents the largest study of AI use in ESS to date. We found the ORR to be more modest than previously reported. The majority of pts had prolonged stable disease with a DCR of 58% even in stage 4 disease. Pts who progress on one AI may benefit from trial of a 2nd AI. A phase 2 study of interruption versus maintenance AI in locally advanced/metastatic ESS is currently underway (NCT03624244).

Economics of Twin Pregnancies in Dairy Cattle

Twinning in Holstein dairy cows has increased over time concurrent with increased milk production. Twinning in dairy cattle is not desirable due to the negative effects on both cows that calve twins and calves born as twins that result in economic losses to dairy farms. Although a twin pregnancy could bring additional income from extra calves and shorten gestation length, twinning compromises milk production, increases the incidence of dystocia and perinatal mortality, decreases calf birth weight, increases the incidence of metabolic diseases, decreases fertility, increases the incidence of freemartinism, increases overall culling risks, and shortens the productive lifespan of cows. Based on a summary of economic analyses from several studies, the estimated losses due to twinning range between $59 to $161 per twin pregnancy. Most twinning in dairy cows is dizygotic and directly related to the incidence of double ovulations, and economic losses are greater for unilateral than for bilateral twins. Hormonal manipulation before artificial insemination that allows for timed artificial insemination is a primary strategy for decreasing twinning in dairy cows before it occurs by decreasing the incidence of double ovulation thereby decreasing conception of dizygotic twins and the associated negative economic consequences. When twins are diagnosed early during gestation, management options might include doing nothing, terminating the pregnancy, or attempting manual embryo reduction. Based on a recent economic analysis of these options, attempting manual embryo reduction decreased the economic losses of a twin pregnancy by $23 to $45.

Periodic Severe Angioedema without Exogenous Hormone Exposure

Hereditary angioedema (HAE) is characterized by recurrent attacks of skin and mucosal swelling in any part of the body including the digestive and respiratory tract which generally improve spontaneously within 12-72 hours. The underlying mechanism in HAE is related to bradykinin dysregulation which causes these attacks not to respond to common treatment strategies including epinephrine or corticosteroid. There are several types of HAE with different etiology but with the same clinical picture. Type 1 is due to the deficiency of C1 Inhibitor (C1- INH) protein and type 2 is related to dysfunctional C1-INH protein. The third type of HAE which comprises the minority of cases is associated with the normal amount and function of C1- INH protein. The presented case in this report was a 15-years old girl with a history of spontaneous angioedema attacks from the age of 14. The frequency of attacks was initially every two months but consequently increased to every two weeks after using some hormonal medications for ovarian cyst. Each episode has lasted around 10 days without any symptoms in between. Complement studies including C4, C1q, and C1-INH protein, both quantitative and qualitative, were reported as normal. A genetic assessment revealed a mutation in the exon 9 on the gene related to factor XII, hence the diagnosis of HAE type 3 was confirmed. This was a rare type of angioedema with normal amount and function of C1-INH protein which is predominantly seen in women during periods of imbalanced estrogen increments like pregnancy, lactation, and menopause, and hence it is responsive to hormonal manipulation strategies such as the use of progesterone containing medications.

Can local treatment prolong the sensitivity of metastatic prostate cancer to androgen deprivation or even prevent castration resistance?

Purpose A number of observational clinical studies suggest that prior primary tumor treatment favorably influences the course of metastatic prostate cancer (PCa), but its mechanisms of action are still speculative. Here, we describe the long-lasting sensitivity to various forms of androgen deprivation in patients after radical prostatectomy (RP) for locally advanced PCa as one potential mechanism. Methods A consecutive series of 115 radical prostatectomies after inductive therapy for T4 prostate cancer was re-analyzed, and long-term survival, as well as recurrence patterns and responses to different forms of hormonal manipulation, were assessed. Results The estimated biochemical response-free, PCa-specific, and overall survival rates after 200 months were 20%, 65%, and 47% with a median overall survival of 156 months. The majority of patients, although not cured of locally advanced PCa (84/115), showed long-term survival after RP. PCa-specific and overall survival rates of these 84 patients with biochemical recurrence were 61% and 44% at 150 months. Long-term sensitivity to ADT was found to be the main reason for the favorable tumor-specific survival in spite of biochemical recurrence. Conclusions Sensitivity to primary or secondary hormonal manipulation was the main reason for the long-term survival of patients who had not been cured by surgery only. The results suggest that treatment of the primary tumor-bearing prostate delays castration-resistant PCa and enhances the effect of hormonal therapies in a previously unknown manner. The underlying cellular and molecular mechanisms need to be explored in more detailed analyses, which could profoundly impact treatment concepts of locally advanced and metastatic PCa.