Delayed Puberty and Estrogen Resistance in a Woman with Estrogen Receptor α Variant

Quaynor, Samuel D.; Stradtman, Earl W.; Kim, Hyung Goo; Shen, Yiping; Chorich, Lynn P.; Schreihofer, Derek A.; Layman, Lawrence C.

doi:10.1056/nejmoa1303611

Cited by 137 publications

(116 citation statements)

References 24 publications

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“…These two sex steroid receptors are also required for side branching of the ductal network, expansion of lobular tissue and terminal differentiation of alveolar MECs to generate milk-producing lobular units during pregnancy (Lydon et al 1995, Hewitt et al 2002, Feng et al 2007, LaMarca & Rosen 2008, Aupperlee et al 2013, Lain et al 2013, Quaynor et al 2013, Sampayo et al 2013. In the absence of pregnancy in rodents and humans, a small degree of glandular expansion and differentiation occurs with every menstrual cycle (Robinson et al 1995).…”

Section: Role Of Ar In Normal Mammary Gland Functionmentioning

confidence: 99%

Bringing androgens up a NOTCH in breast cancer

Tarulli

Butler

Tilley

et al. 2014

Endocrine-Related Cancer

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While it has been known for decades that androgen hormones influence normal breast development and breast carcinogenesis, the underlying mechanisms have only been recently elucidated. To date, most studies have focused on androgen action in breast cancer cell lines, yet these studies represent artificial systems that often do not faithfully replicate/ recapitulate the cellular, molecular and hormonal environments of breast tumours in vivo. It is critical to have a better understanding of how androgens act in the normal mammary gland as well as in in vivo systems that maintain a relevant tumour microenvironment to gain insights into the role of androgens in the modulation of breast cancer development. This in turn will facilitate application of androgen-modulation therapy in breast cancer. This is particularly relevant as current clinical trials focus on inhibiting androgen action as breast cancer therapy but, depending on the steroid receptor profile of the tumour, certain individuals may be better served by selectively stimulating androgen action. Androgen receptor (AR) protein is primarily expressed by the hormone-sensing compartment of normal breast epithelium, commonly referred to as oestrogen receptor alpha (ERa (ESR1))-positive breast epithelial cells, which also express progesterone receptors (PRs) and prolactin receptors and exert powerful developmental influences on adjacent breast epithelial cells. Recent lineage-tracing studies, particularly those focussed on NOTCH signalling, and genetic analysis of cancer risk in the normal breast highlight how signalling via the hormone-sensing compartment can influence normal breast development and breast cancer susceptibility. This provides an impetus to focus on the relationship between androgens, AR and NOTCH signalling and the crosstalk between ERa and PR signalling in the hormone-sensing component of breast epithelium in order to unravel the mechanisms behind the ability of androgens to modulate breast cancer initiation and growth.

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Section: Role Of Ar In Normal Mammary Gland Functionmentioning

confidence: 99%

Bringing androgens up a NOTCH in breast cancer

Tarulli

Butler

Tilley

et al. 2014

Endocrine-Related Cancer

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“…The ESR1 rs2234693 polymorphism (PVUII intron 1) has been linked to height during puberty [31, 32] and adulthood [33, 34]. Furthermore, recessive germline ESR1 mutations causing estrogen resistance and marked pubertal growth delays have been reported in 2 unrelated patients [35, 36].…”

Section: Discussionmentioning

confidence: 99%

Genetic Polymorphisms Associated with Idiopathic Short Stature and First-Year Response to Growth Hormone Treatment

Quigley

Brown

et al. 2019

Horm Res Paediatr

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Background/Aims: The term idiopathic short stature (ISS) describes short stature of unknown, but likely polygenic, etiology. This study aimed to identify genetic polymorphisms associated with the ISS phenotype, and with growth response to supplemental GH. Methods: Using a case-control analysis we compared the prevalence of “tall” versus “short” alleles at 52 polymorphic loci (17 in growth-related candidate genes, 35 identified in prior genome-wide association studies of adult height) in 94 children with ISS followed in the Genetics and Neuroendocrinology of Short Stature International Study, versus 143 controls from the Fels Longitudinal Study. Results: Four variants were nominally associated with ISS using a genotypic model, confirmed by a simultaneous confident inference approach: compared with controls children with ISS had lower odds of “tall” alleles (odds ratio, 95% CI) for GHR (0.52, 0.29–0.96); rs2234693/ESR1 (0.50, 0.25–0.98); rs967417/BMP2 (0.39, 0.17–0.93), and rs4743034/ZNF462 (0.40, 0.18–0.89). Children with ISS also had lower odds of the “tall” allele (A) at the IGFBP3 –202 promoter polymorphism (rs2855744; 0.40, 0.20–0.80) in the simultaneous confident inference analysis. A significant association with 1st-year height SD score increase during GH treatment was observed with rs11205277, located near 4 known genes: MTMR11, SV2A, HIST2H2AA3, and SF3B4; the latter, in which heterozygous mutations occur in Nager acrofacial dysostosis, appears the most relevant gene. Conclusions: In children with ISS we identified associations with “short” alleles at a number of height-related loci. In addition, a polymorphic variant located near SF3B4 was associated with the GH treatment response in our cohort. The findings in our small study warrant further investigation.

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“…Human ER mutations are extremely rare, with only one male out of two cases reported to date [4,109]. The patient had normal male genitalia with bilateral descended testes and a normal sperm count, but the sperm motility was quite low (18 % compared with a normal motility of [50 %), which compromises the sperm quality and suggests impaired male fertility/subfertility [4].…”

Section: Er Mutationsmentioning

confidence: 97%

Oestrogen action and male fertility: experimental and clinical findings

Jia

et al. 2015

Cell. Mol. Life Sci.

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A proper balance between androgen and oestrogen is fundamental for normal male reproductive development and function in both animals and humans. This balance is governed by the cytochrome P450 aromatase, which is expressed also under spatio-temporal control. Oestrogen receptors ERα and/or ERβ, together with the membrane-associated G-protein-coupled functional ER (GPER), mediate the effects of oestrogen in the testis. Oestrogen action in male reproduction is more complex than previously predicted. The androgen/oestrogen balance and its regulation in the masculinisation programming window (MPW) during foetal life is the most critical period for the development of the male reproductive system. If this balance is impaired during the MPW, the male reproductive system may be negatively affected. Recent data from genetically modified mice and human infertile patients have shown that oestrogens may promote the engulfment of live Leydig cells by macrophages leading to male infertility. We also discuss recent data on environmental oestrogen exposure in men and rodents, where a rodent-human distinction is crucial and analyse some aspects of male fertility potentially related to impaired oestrogen/androgen balance.

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Delayed Puberty and Estrogen Resistance in a Woman with Estrogen Receptor α Variant

Cited by 137 publications

References 24 publications

Bringing androgens up a NOTCH in breast cancer

Bringing androgens up a NOTCH in breast cancer

Genetic Polymorphisms Associated with Idiopathic Short Stature and First-Year Response to Growth Hormone Treatment

Oestrogen action and male fertility: experimental and clinical findings

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