Impact of Estrogen Withdrawal and Replacement in Female Mice along the Intestinal Tract. Comparison of E2 Replacement with the Effect of a Mixture of Low Dose Pollutants

Postmenopausal women represent a vulnerable population towards endocrine disruptors due to hormonal deficit. We previously demonstrated that chronic exposure of ovariectomized C57Bl6/J mice fed a high-fat, high-sucrose diet to a low-dose mixture of chemicals with one dioxin, one polychlorobiphenyl, one phthalate, and bisphenol A triggered metabolic alterations in the liver but the intestine was not explored. Yet, the gastrointestinal tract is the main route by which pollutants enter the body. In the present study, we investigated the metabolic consequences of ovarian withdrawal and E2 replacement on the various gut segments along with investigating the impact of the mixture of pollutants. We showed that genes encoding estrogen receptors (Esr1, Gper1 not Esr2), xenobiotic processing genes (e.g., Cyp3a11, Cyp2b10), and genes related to gut homeostasis in the jejunum (e.g., Cd36, Got2, Mmp7) and to bile acid biosynthesis in the gut (e.g., Fgf15, Slc10a2) and liver (e.g., Abcb11, Slc10a1) were under estrogen regulation. Exposure to pollutants mimicked some of the effects of E2 replacement, particularly in the ileum (e.g., Esr1, Nr1c1) suggesting that the mixture had estrogen-mimetic activities. The present findings have important implications for the understanding of estrogen-dependent metabolic alterations with regards to situations of loss of estrogens as observed after menopause.

Migraine Associated with Menstruation An Overlooked Trigger

Menstrual migraine is a condition in females, where headaches are linked with menstruation and may be debilitating. Hormonal fluctuations could have a key role in migraine etiopathogenesis, as several women experience that their migraine attacks correlate with their menstrual cycle. Estrogen withdrawal appears to have a significant role in migraine associated with menstrual cycles, despite the fact that its pathophysiology is not well known. The treatment method can also vary from that used to treat nonmenstrual migraines. However, with proper identification and management of the condition, it can be bearable. This article highlights some portions of what is known about migraine, its triggers including the experience of a sufferer and aims to provide readers with a better understanding of migraine in women by understanding these aspects of the condition.

Cyclical Premenstrual Psychosis - Sometimes It Is Your Hormones

Background: Menstrual psychosis is a broad term used to describe a number of disorders characterized by the acute onset of psychotic symptoms with brief duration, complete resolution of symptoms between episodes, with timing related to menses. This entity was first described in the 18th century, with only 27 confirmed cases using strict diagnostic criteria. While research into causation is limited, estrogen withdrawal is thought to precipitate psychotic symptoms. We describe a case of premenstrual psychosis successfully treated with use of transdermal hormonal contraception and extended menstrual cycling. Clinical Case: A 25-year-old non-binary biologic female (they/them/theirs) with bipolar disorder, anxiety, and psychogenic non-epileptiform seizures was referred to endocrinology for evaluation of recurrent psychotic symptoms associated with menses. They endorsed stable mental health symptoms on aripiprazole except during the seven days prior to their menstrual cycle. During this time they reported persistent auditory hallucinations along with dysmenorrhea, with symptoms resolving at the onset of menses. Timing of menarche was uncertain, however they reported oligomenorrhea until beginning oral contraceptives at age nineteen, after which they developed regular monthly cycles accompanied by psychotic symptoms. Pituitary and ovarian hormone levels were unable to be assessed due to hormonal contraception. Prolactin was 8.3 ng/mL (3-30 ng/mL). In order to limit hormonal fluctuations from daily oral contraceptive pills and monthly withdrawal, the decision was made to transition to transdermal norelgestromin and ethinyl estradiol patches changed weekly, with extended cycling to allow one menstrual cycle every three months. At follow-up visit nine months later they reported resolution of auditory hallucinations on this regimen, with symptoms recurring only during extreme stress. Conclusions: While the etiology of menstrual psychosis is unclear, described treatments include a combination of neuroleptics and hormonal therapy, including estrogen, progesterone, and GnRH agonists. As symptoms did not resolve until suppression of monthly menstrual cycles, this case supports the estrogen withdrawal hypothesis. Our case adds to the literature both in that transdermal, rather than oral or injectable therapy was used, and treatment was successful in alleviating the patient’s psychotic symptoms, improving their mental health and quality of life. References: (1) Brockington, I. Menstrual Psychosis. World Psychiatry 2005;4(1):9-17. (2) Reilly, T.J., Sagnay de la Bastida, V.C., Joyce, D.W., Cullen, A.E., McGuire, P. Exacerbation of Psychosis During the Perimenstrual Phase of the Menstrual Cycle: Systematic Review and Meta-analysis. Schizophrenia Bulletin 2020;46(1):78-90.

Estrogen withdrawal alters cytoskeletal and primary ciliary dynamics resulting in increased Hedgehog and osteoclastogenic paracrine signalling in osteocytes

Estrogen deficiency during post-menopausal osteoporosis leads to osteoclastogenesis and bone loss. Increased pro-osteoclastogenic signalling (RANKL/OPG) by osteocytes occurs following estrogen withdrawal (EW) and is associated with impaired focal adhesions (FAs) and a disrupted actin cytoskeleton. RANKL production is mediated by Hedgehog signalling in osteocytes, a signalling pathway associated with the primary cilium, and the ciliary structure is tightly coupled to the cytoskeleton. Therefore, the objective of this study was to investigate the role of the cilium and associated signalling in EW-mediated osteoclastogenic signalling in osteocytes. We report that EW leads to an elongation of the cilium and increase in Hedgehog and osteoclastogenic signalling. Significant trends were identified linking cilia elongation with reductions in cell area and % FA area/cell area, indicating that cilia elongation is associated with disruption of FAs and actin contractility. To verify this, we inhibited FA assembly via αvβ3 antagonism and inhibited actin contractility and demonstrated an elongated cilia and increased expression of Hh markers and Rankl expression. Therefore, our results suggest that the EW conditions associated with osteoporosis lead to a disorganisation of αvβ3 integrins and reduced actin contractility, which were associated with an elongation of the cilium, activation of the Hh pathway and osteoclastogenic paracrine signalling.

The complex relationship between estrogen and migraines: a scoping review

Background Migraines are a chronic disease for millions worldwide and have been hypothesized to be hormonally mediated due to their higher prevalence in females and menstrual associations. Estrogen has been commonly implicated in migraine pathogenesis, yet its exact role in the pathophysiology of migraines has yet to be fully understood. Method We conducted a scoping review of the literature regarding estrogen’s role in migraine pathogenesis and included 19 studies out of an initial 202 in the final review. Two independent reviewers screened and extracted data from included studies based on predetermined inclusions and exclusion criteria. Results The estrogen withdrawal hypothesis, discussed by 12 of the reviewed studies, is the most discussed theory about estrogen’s role in migraine physiology and describes the association of migraine onset with natural declines in estrogen levels, particularly when estrogen levels fall below 45–50 pg/mL after an extended period of priming. Additional findings suggest that women with a history of migraine have an increased sensitivity to physiologic fluctuations in estradiol levels. Several studies suggest that migraines are associated with menstruation. Conclusion It appears that estrogen is very likely to play a key role in migraine pathogenesis, but seems to affect patients in different ways depending on their past medical history, age, and use of hormonal therapy. Further research is warranted to isolate the effects of estrogen in each unique patient population, and we believe that studies comparing menstruating women to postmenopausal women could help shed light in this area.

The Complex Relationship between Estrogen and Migraines: A Scoping Review

Background: Migraines are a chronic disease for millions worldwide and have been hypothesized to be hormonally mediated due to their higher prevalence in females and menstrual associations. Estrogen has been commonly implicated in migraine pathogenesis yet its exact role in the pathophysiology of migraines has yet to be fully understood.Method: We conducted a scoping review of the literature regarding estrogen’s role in migraine pathogenesis and included 19 studies out of an initial 202 in the final review. Two independent reviewers screened and extracted data from included studies based on predetermined inclusions and exclusion criteria.Results: The estrogen withdrawal hypothesis, discussed by 12 of the reviewed studies, is the most discussed theory about estrogen’s role in migraine physiology and describes the association of migraine onset with natural declines in estrogen levels, particularly when estrogen levels fall below 45-50 pg/mL after an extended period of priming. Additional findings suggest that women with a history of migraine have an increased sensitivity to physiologic fluctuations in estradiol levels. Several studies suggest that migraines are associated with menstruation.Conclusion: It appears that estrogen is very likely to play a key role in migraine pathogenesis, but seems to affect patients in different ways depending on their past medical history, age, and use of hormonal therapy. Further research is warranted to isolate the effects of estrogen in each unique patient population, and we believe that studies comparing menstruating women to postmenopausal women could help shed light in this area.Systematic Review registrations: none

Exosomal miR-186 derived from BMSCs promote osteogenesis through hippo signaling pathway in postmenopausal osteoporosis

Background Postmenopausal osteoporosis (PMO) that results from estrogen withdrawal is the most common primary osteoporosis among older women. However, little is known about the mechanism of PMO, and effective treatment of PMO is limited. Methods We used real-time polymerase chain reaction (qPCR), Western blotting, and RNA pull down to investigate the relationship between miR-186 and MOB Kinase Activator 1A (Mob1). Also, we investigated the effect of exosome in osteogenesis using alkaline phosphatase (ALP) staining. And hematoxylin eosin (HE) staining was used to verify the osteogenesis in PMO model. Results Exosomal miR-186 plays an important role in bone formation. The results of miRNA-seq and q-PCR showed that miR-186 was upregulated in a PMO + Exo treatment group. Results of RNA-pull down and luciferase reporter assays verified interactions between miR-186 and Mob1. We also verified the Hippo signaling pathway plays an important role in osteogenesis. Conclusions We concluded that exosomes derived from human bone marrow mesenchymal stem cells (hBMSCs) can transfer miR-186 to promote osteogenesis in ovariectomy (OVX) rats through the Hippo signaling pathway.

A Potential Involvement of Anandamide in the Modulation of HO/NOS Systems: Women, Menopause, and “Medical Cannabinoids”

Endocannabinoids and their receptors are present in the cardiovascular system; however, their actions under different pathological conditions remain controversial. The aim of our study was to examine the effects of anandamide (AEA) on heme oxygenase (HO) and nitric oxide synthase (NOS) systems in an estrogen-depleted rat model. Sham-operated (SO) and surgically induced estrogen-deficient (OVX) female Wistar rats were used. During a two-week period, a group of OVX rats received 0.1 mg/kg estrogen (E2) per os, while AEA-induced alterations were analyzed after two weeks of AEA treatment at the dose of 1.0 mg/kg. At the end of the experiment, cardiac activity and expression of HO and NOS enzymes, content of cannabinoid 1 receptor, as well as concentrations of transient potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP) were measured. Our results show that estrogen withdrawal caused a significant decrease in both NOS and HO systems, and a similar tendency was observed regarding the TRPV1/CGRP pathway. Two weeks of either AEA or E2 treatment restored the adverse changes; however, the combined administration of these two molecules did not result in a further improvement. In light of the potential relationship between AEA and HO/NOS systems, AEA-induced upregulation of HO/NOS enzymes may be a therapeutic strategy in estrogen-deficient conditions.

The Complex Relationship between Estrogen and Migraines: A Scoping Review

Background:Migraine headaches are a chronic and complex medical issue for millions of patients worldwide. Despite how common migraines are, there is much to be unveiled regarding their pathogenesis due to the numerous factors implicated in the pathophysiology of migraines. Migraines are significantly more common in women and many female migrainers notice menstrual associations of their headaches. Because of this, migraines have popularly been hypothesized to be largely hormonally mediated. Estrogen has been commonly implicated in migraine pathogenesis yet its exact role in the pathophysiology of migraines has yet to be fully understood. Methods: We conducted a scoping review of the literature regarding estrogen’s role in migraine pathogenesis and included 11 studies out of an initial 199 in the final review. Results: The estrogen withdrawal hypothesis is the most discussed theory about estrogen’s role in migraine physiology and describes the association of migraine onset with natural declines in estrogen levels. Estrogen is also implicated in biochemical pain pathways, and specifically effects pain processing, trigeminal nociception, and neural inflammatory peptides. Human studies have been conducted in female populations such as pregnant women and postmenopausal women, and these studies have supported the estrogen withdrawal hypothesis.Conclusions: Hormone replacement therapy remains to treat migraines is promising, yet still lacks definitive evidence in its efficacy. More primary research into estrogen’s mechanisms in migraine pathogenesis is needed, as its specific roles are still unclear. While human-based, clinical trials on the subject are rare, they would provide great insight into migraines and would allow clinicians to better treat patients. Systematic Review registrations: none