Functional similarity between TGF-beta type 2 and type 1 receptors in the female reproductive tract.

Transforming growth factor ß (TGFß) signaling plays critical roles in reproductive development and function. TGFß ligands signal through the TGFß receptor type 2 (TGFBR2)/TGFBR1 complex. As TGFBR2 and TGFBR1 form a signaling complex upon ligand stimulation, they are expected to be equally important for propagating TGFß signaling that elicits cellular responses. However, several genetic studies challenge this concept and indicate that disruption of TGFBR2 or TGFBR1 may lead to contrasting phenotypic outcomes. We have shown that conditional deletion of Tgfbr1 using anti-Mullerian hormone receptor type 2 (Amhr2)-Cre causes oviductal and myometrial defects. To determine the functional requirement of TGFBR2 in the female reproductive tract and the potential phenotypic divergence/similarity resulting from conditional ablation of either receptor, we generated mice harboring Tgfbr2 deletion using the same Cre driver that was previously employed to target Tgfbr1. Herein, we found that conditional deletion of Tgfbr2 led to a similar phenotype to that of Tgfbr1 deletion in the female reproductive tract. Furthermore, genetic removal of Tgfbr1 in the Tgfbr2-deleted uterus had minimal impact on the phenotype of Tgfbr2 conditional knockout mice. In summary, our results reveal the functional similarity between TGFBR2 and TGFBR1 in maintaining the structural integrity of the female reproductive tract.

Imaging in gynecological disease (21): clinical and ultrasound characteristics of accessory cavitated uterine malformations.

OBJECTIVE: To describe the clinical and ultrasound characteristics of accessory cavitated uterine malformations (ACUMs). METHODS: This was a single-center observational study of consecutive patients diagnosed with an ACUM, who had undergone an ultrasound examination by an experienced ultrasound examiner between January 2013 and May 2019, identified retrospectively from medical records. ACUM was diagnosed when a cavitated lesion with a myometrial mantle and echogenic contents was seen within the anterolateral wall of the myometrium beneath the insertion of the round ligament. In all women, presenting symptoms and clinical history were recorded along with detailed descriptions of the lesions and any concomitant pelvic abnormalities. RESULTS: Twenty patients diagnosed with an ACUM were identified. Median age was 29.2 (interquartile range, 25.0-35.8) years. None of the women was premenarchal or postmenopausal. All of the women reported painful periods or pelvic pain and none of them reported subfertility. Twelve of the ACUMs were in the right anterolateral myometrium and eight were in the left anterolateral myometrium. Both a myometrial mantle and a fluid-filled cavity were considered to be defining features on ultrasound. The fluid contained within the cavity was either echogenic with a ground-glass appearance or hyperechoic. All of the lesions were spherical in shape. The Doppler flow seen in the outer rim was not markedly different from that of the surrounding myometrium, and the content of the cavity was avascular on Doppler examination. The mean outer cavity diameter of the ACUMs was 22.8 (95% CI, 20.9-24.8) mm and the mean internal cavity diameter was 14.1 (95% CI, 12.2-16.1) mm. Four women opted for transvaginal ultrasound-guided alcohol sclerotherapy. Surgical excision was carried out in eight cases, and the diagnosis was confirmed on histopathological examination in all of them. CONCLUSIONS: ACUMs are a uterine abnormality with a distinct ultrasound appearance, which are associated with dysmenorrhea and chronic pelvic pain. Knowledge of their typical appearance on ultrasound could facilitate early detection and treatment. There are several treatment options for ACUM, ranging from simple analgesia to complete excision. Further prospective and longitudinal studies are required to study the prevalence and natural history of this condition. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Targeted ablation of Wnt4 and Wnt5a in Müllerian duct mesenchyme impedes endometrial gland development and causes partial Müllerian agenesis.

Wnt4 and Wnt5a have well-established roles in the embryonic development of the female reproductive tract, as well as in implantation, decidualization, and ovarian function in adult mice. Although these roles appear to overlap, whether Wnt5a and Wnt4 are functionally redundant in these tissues has not been determined. We addressed this by concomitantly inactivating Wnt4 and Wnt5a in the Müllerian mesenchyme and in ovarian granulosa cells by crossing mice bearing floxed alleles to the Amhr2cre strain. Whereas fertility was reduced by ∼50% in Wnt4flox/flox; Amhr2cre/+ and Wnt5aflox/flox; Amhr2cre/+ females, Wnt4flox/flox; Wnt5aflox/flox; Amhr2cre/+ mice were either nearly or completely sterile. Loss of fertility was not due to an ovarian defect, as serum ovarian hormone levels, follicle counts, and ovulation rates were comparable to controls. Conversely, the uterus was abnormal in Wnt4flox/flox; Wnt5aflox/flox; Amhr2cre/+ mice, with thin myometrial and stromal layers, frequent fibrosis and a >90% reduction in numbers of uterine glands, suggesting redundant or additive roles of Wnt4 and Wnt5a in uterine adenogenesis. Loss of fertility in Wnt4flox/flox; Wnt5aflox/flox; Amhr2cre/+ mice was attributed to defects in decidualization, implantation, and placental development, the severity of which were proportional to the extent of gland loss. Furthermore, a third of Wnt4flox/flox; Wnt5aflox/flox; Amhr2cre/+ females had a partial agenesis of Müllerian duct-derived structures, but with normal oviducts and ovaries. Together, our results suggest that Wnt4 and Wnt5a play redundant roles in the development of the female reproductive tract, and may provide insight into the etiology of certain cases of Müllerian agenesis in women.

Defect in the uterine wall with prolapse of amniotic sac into it at 32 weeks' gestation in a primigravida woman without any previous uterine surgery.

We experienced a case of uterine wall defect with amniocele in a primigravida woman without any history of uterine surgery. On admission due to acute abdominal pain at 32 weeks' gestation, an ultrasound examination showed a 9 × 7-cm sized echogenic cystic area in the Morrison pouch. Color Doppler revealed a flow from the uterus into the cystic area through a myometrial defect. During the operation, a 1-cm defect in the uterine myometrium was found on the right fundus. An intact amniotic sac was prolapsed into the abdominal cavity through the myometrial defect. This was an extremely rare case of unexplained uterine wall defect.

CTNNB1 in mesenchyme regulates epithelial cell differentiation during Müllerian duct and postnatal uterine development.

Müllerian duct differentiation and development into the female reproductive tract is essential for fertility, but mechanisms regulating these processes are poorly understood. WNT signaling is critical for proper development of the female reproductive tract as evident by the phenotypes of Wnt4, Wnt5a, Wnt7a, and ß-catenin (Ctnnb1) mutant mice. Here we extend these findings by determining the effects of constitutive CTNNB1 activation within the mesenchyme of the developing Müllerian duct and its differentiated derivatives. This was accomplished by crossing Amhr2-Cre knock-in mice with Ctnnb1 exon (ex) 3(f/f) mice. Amhr2-Cre(Δ/+); Ctnnb1 ex3(f/+) females did not form an oviduct, had smaller uteri, endometrial gland defects, and were infertile. At the cellular level, stabilization of CTNNB1 in the mesenchyme caused alterations within the epithelium, including less proliferation, delayed uterine gland formation, and induction of an epithelial-mesenchymal transition (EMT) event. This EMT event is observed before birth and is complete within 5 days after birth. Misexpression of estrogen receptor α in the epithelia correlated with the EMT before birth, but not after. These studies indicate that regulated CTNNB1 in mesenchyme is important for epithelial cell differentiation during female reproductive tract development.

Loss of APC function in mesenchymal cells surrounding the Müllerian duct leads to myometrial defects in adult mice.

The WNT signal transduction pathway plays a rate limiting role in early development of many different organs. To study the functional consequences of constitutive activation of the canonical WNT pathway in the developing uterus, we generated a novel mouse model where loss of the tumor suppressor gene Apc was induced. A mouse model was generated and evaluated where Amhr2(Cre/+) driven loss of Apc exon 15 was induced. The Apc recombination was detected mainly in the myometrial layer of the adult uterus. A significant loss of muscle fibers in myometrium was apparent, though with very few muscle cells earmarked by nuclear ß-catenin. The finding was confirmed in the Pgr(Cre/+);Apc(15lox/15lox) mouse model. Loss of APC function in mesenchymal cells surrounding the fetal Müllerian ducts results in severe defects in the myometrial layers of the uterus in adult mice, suggesting that the WNT signaling pathway plays important roles in maintaining myometrial integrity.

Is hysteroscopic correction of an incomplete uterine septum justified prior to IVF?

This retrospective study examined the effect of hysteroscopic correction of an incomplete uterine septum on IVF outcome. Measurement of the Fm (fundal myometrial thickness) and Cm (cornual myometrial thickness) was performed by sonohysterography. Group 1 included patients diagnosed with incomplete septum (n = 119), fulfilling the two criteria of Fm >11 mm and Fm-Cm >5 mm, who underwent hysteroscopic incision of the incomplete septum. Group 2 consisted of 116 age-matched control patients with a normal uterine cavity who underwent IVF within the same time period. Main outcome measures were clinical pregnancy and spontaneous abortion rates. Patients in group 1 had a history of more spontaneous abortions than patients in group 2 (14.20 versus 6.03%, P = 0.04) as well as higher previous IVF failure (32.7 versus 20.6%, P = 0.04). After surgical correction of the septum in group 1, IVF pregnancy outcome was similar in both groups (clinical pregnancy and pregnancy loss of 47.80 versus 46.50% and 10.52 versus 20.3% respectively). A similar pregnancy outcome was found after the incision of the incomplete septum compared with a group with normal uterine cavity. Larger prospective and randomized controlled studies are needed to prove the positive effect of correction of an incomplete uterine septum on IVF outcome.

[Abdominal metroplasty: 25 years experience]. / Abdominalis metroplastica: 25 éves tapasztalat.

INTRODUCTION: The congenital or acquired anomalies of uterus could be the causes of complications in obstetrics. PATIENTS AND METHODS: 157 patients were diagnosed by hysterosalpingography and/or ultrasound as having subseptate uterus which were assumed to be responsible for their recurrent abortions (124 cases) or infertility (33 cases), and who have not had children yet. RESULTS: During the last 25 years 157 abdominal metroplasties without the excision of the septum was performed: 99 became pregnant at least once, of their 142 pregnancies 117 continued to the at least 37th gestational weeks (all but five with delivery by cesarean section). Altogether 122 healthy newborn infants were born. CONCLUSIONS: Conventional abdominal metroplasty seems to be an operation which clearly improves fetal survival rate in women with both symmetric uterine malformations and a history of habitual abortions. Subsequent pregnancies are not associated with any increased risk of complications. Abdominal metroplasty also seems to be a procedure which improves reproductive performance in women with either subseptate or bicornuate uterus and otherwise unexplained infertility.

[Diffuse myometrial hypertrophy. Cause of abnormal uterine bleeding. Clinico-pathological study of 4 cases and review of the literature]. / Hipertrofia difusa del miometrio. Causa de sangrado uterino anormal. Estudio clinicopatológico de cuatro casos y análisis de la literatura.

Difusse uterine myohipertrophy (DUMH) is a condition characterized by the presence of homogeneous and diffuse uterine enlargement in the absence of myoendometrial cause of bleeding. Today there is insufficient data to conclude that DUMH is a distinct clinicopathological entity. It is characterized by: 1) Uterine weight of more that 200 g, 2) a myometrial thickness of more that 2.0 cm and 3) the absence of any endomyometrial cause of bleeding. In DUMH the increased thickness of the myometrium is due to hypertrophy of the muscle cells with no increase in fibroconnective intersticial tissue and the bleeding secondary to increase endometrial area and abnormal myometrium contraction. We report 4 cases of DUMH seen at the ABC Hospital.