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CC BY-NC-ND 4.0 · Geburtshilfe Frauenheilkd 2017; 77(07): 756-764
DOI: 10.1055/s-0043-111899
GebFra Science
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Insufficient Angiogenesis: Cause of Abnormally Thin Endometrium in Subfertile Patients?

Insuffiziente Angiogenese: Ursache eines abnorm dünnen Endometriums bei subfertilen Patientinnen?
Joachim Alfer
1   Institute of Pathology, Kaufbeuren-Ravensburg, Ravensburg, Germany
,
Lars Happel
2   Institute of Reproductive Medicine, IVF-Saar, Saarbrücken, Germany
,
Ralf Dittrich
3   Department of Obstetrics and Gynecology, Erlangen University Hospital Friedrich-Alexander Universität, Erlangen-Nürnberg, Germany
,
Matthias W. Beckmann
3   Department of Obstetrics and Gynecology, Erlangen University Hospital Friedrich-Alexander Universität, Erlangen-Nürnberg, Germany
,
Arndt Hartmann
4   Department of Pathology, Erlangen University Hospital Friedrich-Alexander Universität, Erlangen-Nürnberg, Germany
,
Andreas Gaumann
1   Institute of Pathology, Kaufbeuren-Ravensburg, Ravensburg, Germany
,
Volker U. Buck
5   Institute of Molecular and Cellular Anatomy, Medical Faculty, RWTH Aachen University, Aachen, Germany
,
Irmgard Classen-Linke
5   Institute of Molecular and Cellular Anatomy, Medical Faculty, RWTH Aachen University, Aachen, Germany
› Author Affiliations
Further Information

Publication History

received 13 April 2017
revised 21 May 2017

accepted 22 May 2017

Publication Date:
17 July 2017 (online)

Also available at
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Abstract

Introduction This study investigated subfertile patients with abnormally thin endometrium after infertility treatment. As they had adequate serum concentrations of hormones, an endometrial factor for subfertility was suspected.

Methods To elucidate the cause of subfertility, endometrial biopsies were taken in each patient in the late proliferative and mid-secretory phases of one menstrual cycle. Endometrial biopsies from women with normal menstrual cycles and confirmed fertility who were undergoing hysterectomy for benign uterine disease were used as positive controls. The tissue samples were investigated for steroid hormone receptor expression and for the proliferation marker Ki-67. Immunohistochemistry was performed with antibodies against the marker molecules for endometrial receptivity – β3 integrin, VEGF, LIF, and CD56 (large granular lymphocytes, LGLs).

Results The steroid hormone receptors for estrogen (E2) and progesterone (P) were expressed normally (at the first biopsy) and were down-regulated (at the second biopsy) within the cycle. Strikingly, all of the marker molecules investigated showed negative or weak and inadequate expression in the mid-secretory phase. Numbers of LGLs remained as low as in the proliferative phase. In contrast, fertile patients were found to express these marker molecules distinctly in the mid-secretory phase.

Conclusions It may be hypothesized that a severe deficiency of these angiogenesis-related marker molecules leads to defective development of the endometrium, which remains thin. Deficient angiogenetic development may thus provide an explanation for the endometrial factor that causes infertility. Further investigations will need to focus on identifying the regulating factors that act between steroid receptor activation and the expression of these marker molecules.

Zusammenfassung

Einleitung Diese Studie untersuchte subfertile Patientinnen mit einem abnorm dünnen Endometrium nach einer Infertilitätsbehandlung. Da ausreichende Hormonkonzentrationen im Blut dieser Frauen gemessen wurden, lag die Vermutung nahe, dass ein endometrialer Faktor für die verminderte Fertilität eine Rolle spielen könnte.

Methoden Um möglichen Ursachen für die verminderte Fertilität auf den Grund zu gehen, wurden bei jeder Patientin Biopsien des Endometriums in der späten Proliferationsphase sowie in der mittleren Sekretionsphase eines Menstruationszyklus durchgeführt. Endometriale Biopsien von fertilen Frauen mit regulärem Menstruationszyklus, die sich einer Hysterektomie wegen gutartiger Gebärmutterveränderungen unterziehen mussten, dienten als Positivkontrollen. Die Gewebeproben wurden auf die Expression von Steroidhormonrezeptoren sowie mit dem Proliferationsmarker Ki-67untersucht. Mithilfe von Antikörpern gegen Markermoleküle der endometrialen Rezeptivität: β3-Integrin, VEGF, LIF und CD56 (große granuläre Lymphozyten, LGLs), wurden immunhistochemische Untersuchungen durchgeführt.

Ergebnisse Die Steroidhormonrezeptoren für Östrogen (E2) und Progesteron (P) waren bei der ersten in einem Zyklus durchgeführten Biopsie normal exprimiert und in der zweiten Biopsie im selben Zyklus herunterreguliert. Auffallend war, dass die Expression aller untersuchten Marker in der mittleren Sekretionsphase negativ oder schwach bzw. ungenügend war. Die Anzahl der LGLs blieb so niedrig wie in der Proliferationsphase. Dagegen wurden diese Markermoleküle bei fertilen Patientinnen in der mittleren Sekretionsphase deutlich exprimiert.

Schlussfolgerungen Es wurde die Hypothese aufgestellt, dass die starke Defizienz dieser Markermoleküle, die in Beziehung zur Angiogenese stehen, zu einer ungenügenden Ausbildung des Endometriums führt, das dann dünn bleibt. Eine unzureichende angiogenetische Entwicklung mag daher der Grund für eine endometriale Insuffizienz sein, die zur Infertilität führt. Weitergehende Studien sind nötig, um die Faktoren zu identifizieren, die zwischen der Steroidrezeptor-Aktivierung und der Expression dieser Markermoleküle regulierend wirken.

Key words

thin endometrium - IVF - LIF - VEGF - β3 integrin - angiogenesis

Schlüsselwörter

dünne Gebärmutterschleimhaut - IVF - LIF - VEGF - β3-Integrin - Angiogenese
 

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