Quantitative differences in TGF-β family members measured in small antral follicle fluids from women with or without PCO

CONTEXT: Members of the Transforming-Growth-Factor-β (TGF-β) family have been implicated in aberrant follicle development in women with polycystic ovaries (PCO). OBJECTIVE: Are there quantitative differences in the concentrations of TGF-β family members in fluid from small antral follicles (hSAF) from women with or without PCO? DESIGN SETTING: & Follicle fluids (FF) were collected from 4-11 mm hSAF obtained from women undergoing ovarian tissue cryopreservation for fertility preservation. PATIENTS: FFs from 16 women with PCO (FF=93) and 33 women without PCO (FF=92). MAIN OUTCOME MEASURES: Intrafollicular concentrations of Growth-Differentiation-Factor-9 (GDF9), Anti-Müllerian-Hormone (AMH), inhibin-A and -B, total inhibin, activin-A, -B and -AB, follistatin, follistatin-like-3, estradiol, and testosterone. RESULTS: Activin-B concentrations are reported for the first time in hSAF and concentrations were 10 times higher than activin-A and -AB. Activin-B showed significant associations to other growth factors. Concentrations of inhibin-A and -B were significantly lower in FF from women with PCO, especially in hSAF below 8 mm in diameter. AMH concentrations did not differ between the groups in hSAF below 8 mm, however, AMH remained high in hSAF above 8 mm in PCO but decreased in non-PCO women. Estradiol was significantly lower in FF from women with PCO and showed significant associations with AMH. Concentrations of GDF9 are reported for the first time showing significantly higher concentrations in PCO FF of follicles above 6 mm. CONCLUSIONS: Altered concentrations of TGF-β family members in hSAF from women with PCO highlight altered growth factor signaling as a potential mechanism for follicle growth arrest

Intrafollicular concentrations of the oocyte-secreted factors GDF9 and BMP15 vary inversely in polycystic ovaries

Context The oocyte-secreted factors growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) play essential roles in follicle development and oocyte maturation, and aberrant regulation might contribute to the pathogenesis of polycystic ovary syndrome. Objective Are there measurable differences in concentrations of GDF9, BMP15, and the GDF9/BMP15 heterodimer in small antral follicle fluids from women with and without polycystic ovaries (PCO)? Design and Setting Follicle fluids (n = 356) were collected from 4- to 11-mm follicles in unstimulated ovaries of 87 women undergoing ovarian tissue cryopreservation for fertility preservation. Patients Twenty-seven women with PCO were identified and 60 women without PCO-like characteristics (non-PCO women) were matched according to age and follicle size. Main outcome measures Intrafollicular concentrations of GDF9, BMP15, GDF9/BMP15 heterodimer, anti-Mullerian hormone (AMH), inhibin-A and -B, total inhibin, activin-B and -AB, and follistatin were measured using enzyme-linked immunosorbent assays. Results The detectability of GDF9, BMP15, and the GDF9/BMP15 heterodimer were 100%, 94.4%, and 91.5%, respectively, and concentrations were significantly negatively correlated with increasing follicle size (P < 0.0001). GDF9 was significantly higher in women with PCO (PCO: 4230 ± 189 pg/mL [mean ± SEM], n = 188; non-PCO: 3498 ± 199 pg/mL, n = 168; P < 0.03), whereas BMP15 was lower in women with PCO (PCO: 431 ± 40 pg/mL, n = 125; non-PCO: 573 ± 55 pg/mL, n = 109; P = 0.10), leading to a significantly higher GDF9:BMP15 ratio in women with PCO (P < 0.01). Significant positive associations between BMP15 and AMH, activins, and inhibins in non-PCO women switched to negative associations in women with PCO. Conclusions Intrafollicular concentrations of GDF9 and BMP15 varied inversely in women with PCO reflecting an aberrant endocrine environment. An increased GDF9:BMP15 ratio may be a new biomarker for PCO

Novel variants in the stem cell niche factor WNT2B define the disease phenotype as a congenital enteropathy with ocular dysgenesis

WNT2B is a member of the Wnt family, a group of signal transduction proteins involved in embryologic development and stem cell renewal and maintenance. We recently reported homozygous nonsense variants in WNT2B in three individuals with severe, neonatal-onset diarrhea, and intestinal failure. Here we present a fourth case, from a separate family, with neonatal diarrhea associated with novel compound heterozygous WNT2B variants. One of the two variants was a frameshift variant (c.423del [p.Phe141fs]), while the other was a missense change (c.722 G > A [p.G241D]) that we predict through homology modeling to be deleterious, disrupting post-translational acylation. This patient presented as a neonate with severe diet-induced (osmotic) diarrhea and growth failure resulting in dependence on parenteral nutrition. Her gastrointestinal histology revealed abnormal cellular architecture particularly in the stomach and colon, including oxyntic atrophy, abnormal distribution of enteroendocrine cells, and a paucity of colonic crypt glands. In addition to her gastrointestinal findings, she had bilateral corneal clouding and atypical genital development later identified as a testicular 46,XX difference/disorder of sexual development. Upon review of the previously reported cases, two others also had anterior segment ocular anomalies though none had atypical genital development. This growing case series suggests that variants in WNT2B are associated with an oculo-intestinal (and possibly gonadal) syndrome, due to the protein’s putative involvement in multiple developmental and stem cell maintenance pathways

Turner Syndrome

Turner syndrome (TS) summarises a heterogeneous group of patients with different chromosomal pathologies, including 45,X0 monosomy, mosaicism and structural abnormalities of the X chromosome. Monosomies usually lead to very early premature ovarian insufficiency, whereas mosaicism and structural abnormalities may preserve fertility. The genotype should therefore be taken into account in the indication for and implementation of a fertility preservation measure. The increased pregnancy risks in Turner syndrome must also be considered. Fertility preservation measures include freezing of oocytes and possibly ovarian tissue