Endometriosis in MRKH cases as a proof for the coelomic metaplasia hypothesis?

A diagnosis of endometriosis is based upon the histological identification of endometrial tissue at ectopic sites which are commonly located on the pelvic organs, the peritoneum and ovary. In rare cases, ectopic lesions can be found in other organs, such as kidney, bladder, lung or brain. Diagnosis is achieved by laparoscopic intervention followed by histological confirmation of endometriotic tissue. Prevalence is estimated at approximately 10% in the general female population with many patients experiencing pain and/or infertility. Currently, the implantation hypothesis by Sampson is the most accepted hypothesis about the pathogenesis of endometriosis. However, the occurrence of endometriosis in patients with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome who sometimes lack a uterus or endometrium seems to suggest metaplasia as a cause of endometriosis. A critical reevaluation of the literature about MRKH does not reveal conclusive evidence of an association of uterus/endometrium agenesis and endometriosis. Most often only MRI diagnoses of uterus/endometrium agenesis and only very rarely conclusive histological evidence of the endometriotic lesions are presented. In contrast, whenever biopsies were performed endometriosis always appeared together with uterus/endometrium remnants. Taken together, we suggest that MRKH patients only develop endometriosis if a uterus/endometrium is present which underscores and not contradicts the implantation hypothesis of Sampson.

Signaling by TGF-betas in tubule cultures of adult rat testis.

Although signal transduction of transforming growth factor-betas (TGF-ßs) is well characterized in individual cell types, data about TGF-ß signaling in a cellular context is still scarce. In this study, we used ex vivo tubule cultures from adult rat testis to investigate TGF-ß signaling. We show for the first time in testicular tubules, that TGF-ßs also signal via the BMP type I receptors, with ALK2 used by TGF-ß1 and ALK3 and ALK6 by TGF-ß2. This signal transduction is mediated via Smad3 as well as via Smad1. In contrast, BMPs (BMP2 and BMP7) do not signal via the high-affinity type I and type II TGFß receptors, TBR1 or TBR2. Furthermore, treatment of tubule cultures with either TGF-ß1 or TGF-ß2 had profound significant stimulatory effects on secretion of plasminogen activator-1 (PAI-1) through utilization of TGF-ß and BMP receptors. Specific inhibitors for either TBR1 or BMP receptors yielded nearly complete inhibition of TGF-ß signaling. The TBR1-TBR2 signalosome was detected with Duolink upon stimulation with either TGF-ß1 or TGF-ß2, predominantly in spermatogenic cells of the adult rat testis, particularly in elongated spermatids. In summary, this examination of intact rat testicular tubules demonstrated for the first time that TGF-ßs signal mainly through TBR1 and TBR2 but also use BMP receptors, including for secretion of PAI-1. Whereas ALK2 participates in the TGF-ß1-induced TBR1-TBR2 signalosome, ALK3 and ALK6 are involved in signaling of TGF-ß2. Detection of the TBR1-TBR2 signalosome in late spermiogenic cells indicates a post-meiotic activity.