Reduced Transforming Growth Factor-β Activity in the Endometrium of Women With Heavy Menstrual Bleeding

Maybin, Jacqueline A; Boswell, Lyndsey; Young, Vikki; Duncan, W. Colin; Critchley, Hilary O. D.

doi:10.1210/jc.2016-3437

Cited by 19 publications

(21 citation statements)

References 24 publications

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“…In addition, they also demonstrated a decrease in Smad2 and Smad3 mRNA and levels of their corresponding phosphoproteins in women with HMB. The findings of the current study are more consistent with those of Maybin et al (2017), and any differences may be due to differences in methodology, menstrual cycle groupings, and classification of HMB. Maybin et al (2017) used an empirical definition of HMB with 80 mL menstrual blood loss as the cut off, whereas blood loss was not objectively measured in our study, and we used the current clinical assessment of patient declared HMB; thus, the classification used in the current study was more subjective.…”

Section: Discussionsupporting

confidence: 79%

“…Abberton et al (1999b) demonstrated no difference in TGFβ1 immunoreactivity in an immunohistochemical study of endometrium from control women and those with HMB. More recently, Maybin et al (2017) reported no difference in mRNA levels for TGFβ1, TGFβRI, or TGFβRII in endometrium of women with HMB compared with controls. However, they did demonstrate a decrease in immunoreactivity for TGFβ1 in the stromal cells of women with HMB compared with controls.…”

Section: Discussionmentioning

confidence: 96%

“…TGFβ1 and its receptors are expressed in the endometrium across the menstrual cycle, and TGFβ1 is also increased in RPL, a condition associated with increased vascular maturation (Lash et al, 2012). Expression of TGFβ1 has previously been shown to be either unchanged (Abberton et al, 1999b) or reduced in the endometrium of women with HMB (Maybin et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Transforming Growth Factor (TGF) β and Endometrial Vascular Maturation

Sun

Shivhare

et al. 2021

Front. Cell Dev. Biol.

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Appropriate growth and development of the endometrium across the menstrual cycle is key for a woman’s quality of life and reproductive well-being. Recurrent pregnancy loss (RPL) and heavy menstrual bleeding (HMB) affect a significant proportion of the female population worldwide. These endometrial pathologies have a significant impact on a woman’s quality of life as well as placing a high economic burden on a country’s health service. An underlying cause for both conditions is unknown in approximately 50% of cases. Previous research has demonstrated that aberrant endometrial vascular maturation is associated with both RPL and HMB, where it is increased in RPL but reduced in HMB. TGFβ1 is one of the key growth factors that regulate vascular maturation, by inducing phenotypic switching of vascular smooth muscle cells (VSMCs) from a synthetic phenotype to a more contractile one. Our previous data demonstrated an increase in TGFβ1 in the endometrium of RPL, while others have shown a decrease in women with HMB. However, TGFβ1 bioavailability is tightly controlled, and we therefore sought to perform an extensive immunohistochemical analysis of different components in the pathway in the endometrium of normal controls, women with HMB or RPL. In addition, two in vitro models were used to examine the role of TGFβ1 in endometrial vascular maturation and endothelial cell (EC):VSMC association. Taken all together, the immunohistochemical data suggest a decrease in bioavailability, receptor binding capacity, and signaling in the endometrium of women with HMB compared with controls. In contrast, there is an increase in the bioavailability of active TGFβ1 in the endometrium of women with RPL compared with controls. Endometrial explants cultured in TGFβ1 had an increase in the number of vessels associated with contractile VSMC markers, although the total number of vessels did not increase. In addition, TGFβ1 increased EC:VSMC association in an in vitro model. In conclusion, TGFβ1 is a key regulator of endometrial vascular maturation and could be considered as a therapeutic target for women suffering from HMB and/or RPL.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Transforming Growth Factor (TGF) β and Endometrial Vascular Maturation

Sun

Shivhare

et al. 2021

Front. Cell Dev. Biol.

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“…Menstrual blood loss (MBL) was objectively measured in the women providing endometrial tissue using a modified alkaline haematin method ( Hallberg & Nilsson 1964 , Maybin et al 2017 ) and heavy menstrual bleeding (HMB) defined as a blood loss of >80 mL per cycle. Women were given the same brand of menstrual products (Tampax® tampons/Always® towels, Proctor & Gamble, UK) with verbal and written instruction on collection.…”

Section: Methodsmentioning

confidence: 99%

Obesity is associated with heavy menstruation that may be due to delayed endometrial repair

Reavey

Walker

Murray

et al. 2021

Journal of Endocrinology

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Heavy menstrual bleeding is common and debilitating but the causes remain ill defined. Rates of obesity in women are increasing and its impact on menstrual blood loss (MBL) is unknown. Therefore, we quantified BMI and MBL in women not taking hormones and with regular menstrual cycles and revealed a positive correlation. In a mouse model of simulated menstruation, diet-induced obesity also resulted in delayed endometrial repair, a surrogate marker for MBL. BrdU staining of mouse uterine tissue revealed decreased proliferation during menstruation in the luminal epithelium of mice on a high-fat diet. Menstruation is known to initiate local endometrial inflammation and endometrial hypoxia; hence, the impact of body weight on these processes was investigated. A panel of hypoxia-regulated genes (VEGF, ADM, LDHA, SLC2A1) showed consistently higher mean values in the endometrium of women with obesity and in uteri of mice with increased weight vs normal controls, although statistical significance was not reached. The inflammatory mediators, Tnf and Il6 were significantly increased in the uterus of mice on a high-fat diet, consistent with a pro-inflammatory local endometrial environment in these mice. In conclusion, obesity was associated with increased MBL in women. Mice given a high-fat diet had delayed endometrial repair at menstruation and provided a model in which to study the influence of obesity on menstrual physiology. Our results indicate that obesity results in a more pro-inflammatory local endometrial environment at menstruation, which may delay endometrial repair and increase menstrual blood loss.

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“…TGFβ1 is involved with phenotype switching of VSM cells to a contractile phenotype and is also required for repair of the denuded menstrual endometrium 101 . There is evidence of decreased TGFβ1 bioavailability and signalling in the endometrium of women with HMB 101,102 , suggesting that TGFβ1 signalling and bioavailability could be potential therapeutic targets for the treatment of HMB in the future.…”

Section: Control Of Endometrial Bleedingmentioning

confidence: 99%