Non-reproductive Effects of Anovulation

 

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Abstract

Introduction: Several authors have linked subclinical ovulatory disturbances in normal length menstrual cycles to premenopausal fracture risk and bone changes. This study systematically examined the influence of ovulation and anovulation on the bone metabolism of premenopausal women. Participants and Methods: In 176 cycles in healthy premenopausal women, FSH, 17β-estradiol (E2) and progesterone (P4) as well as bone alkalic phosphatase (BAP), pyridinoline (PYD) and C-terminal crosslinks (CTX) were measured during the follicular and during the luteal phase. The probability and timing of ovulation was self-assessed by a monitoring device. In addition, bone density of the lumbar spine was measured by quantitative computed tomography (QCT) at baseline and at the end of the study. Analysis was restricted to blood samples taken more than three days before the following menstruation. Results: 118 cycles out of the 176 collected cycles were complete with blood samples taken within the correct time interval. Of these, 56.8 % were ovulatory by two criteria (ovulation symbol shown on the monitor display and LP progesterone > 6 ng/ml), 33.1 % were possibly ovulatory by one criterion (ovulation symbol shown on the monitor display or LP progesterone > 6 ng/ml), and 10.2 % were anovulatory by both criteria). Ovulation in the previous cycle and in the same cycle did not significantly influence the mean absolute concentrations of the bone markers. However, bone formation (BAP) was higher in the luteal phase of ovulatory cycles than in anovulatory cycles (n. s.) and the relative changes within one cycle were significantly different for bone resorption (CTX) during ovulatory vs. anovulatory cycles (p < 0.01). In 68 pairs of cycles following each other directly, both ovulation in the previous cycle and ovulation in the present cycle influenced CTX, but not the differences of other bone markers. Conclusion: Ovulatory cycles reduce bone resorption in their luteal phase and that of the following cycle. The interaction between ovulation and bone metabolism is complex. Since anovulation may occur in low estrogen states such as pre-anorexic dietary restraint, as well as with high estrogenic circumstances e.g. from functional perimenopausal ovarian cysts, the association with bone changes has been variable in the literature. Accumulating physiological and clinical evidence however point towards a role for ovulation in enhancing bone formation and limiting bone resorption.

Zusammenfassung

Einleitung: Sowohl Knochenstoffwechselveränderungen wie auch ein erhöhtes Risiko für spätere Frakturen sind von verschiedenen Autoren mit subklinischen ovulatorischen Störungen (in menstruellen Zyklen normaler Länge) in Verbindung gebracht worden. Diese Pilotstudie untersuchte systematisch den Einfluss der Ovulation und Anovulation auf den Knochenstoffwechsel prämenopausaler Frauen. Studienteilnehmerinnen und Methodik: Bei gesunden prämenopausalen Frauen wurden in 176 Zyklen FSH, 17β-Estradiol (E2) und Progesteron (P4) sowie knochenalkalische Phosphatase (BAP), Pyridinolin (PYD) und C-terminale Crosslinks (CTX) jeweils während Follikelphase und Lutealphase gemessen. Die Ovulations-Wahrscheinlichkeit und der Zeitpunkt der Ovulation wurden mittels Zyklusmonitor bestimmt. Die Knochendichte der Lendenwirbelsäule wurde mit quantitativer Computertomografie (QCT) zu Beginn und am Ende der Studie gemessen. Analysiert wurden die Zyklen, in denen die Lutealphasen-Blutproben mehr als 3 Tage vor der nächsten Menstruation entnommen worden waren. Ergebnisse: In 118 von 176 gesammelten Zyklen waren die Blutproben im korrekten Zeitintervall. 56,8 % wurden auf der Basis von 2 Kriterien (Ovulationssymbol auf der Monitoranzeige und Progesteron > 6 ng/ml) als ovulatorisch gewertet, 33,1 % als möglicherweise ovulatorisch (nur Ovulationssymbol auf der Monitoranzeige oder LP Progesteron > 6 ng/ml) und 10,2 % als anovulatorisch (nach beiden Kriterien) klassifiziert. Die relativen Unterschiede innerhalb eines Zyklus (LP – FP) waren für den Knochenabbau-Marker CTX in ovulatorischen vs. anovulatorischen Zyklen signifikant vermindert (p < 0,01). In 68 Zykluspaaren, die direkt aufeinander folgten, beeinflussten sowohl die Ovulation im vorangegangenen als auch die Ovulation im aktuellen Zyklus signifikant den Knochenabbau-Parameter CTX, die intrazyklischen Unterschiede anderer Knochenmarker erreichten in dieser Pilotstudie keine Signifikanz. Diskussion: Die Interaktion zwischen Ovulation und Knochenstoffwechsel ist komplex. Ovulatorische Zyklen reduzieren den Knochenabbau in der Lutealphase des gleichen Zyklus und der des nachfolgenden Zyklus. Dadurch dass Anovulation mit niedrigen Estrogenspiegeln (z. B. prä-anorektische Ernährung) ebenso auftritt wie in Verbindung mit hohen Östrogenspiegeln (z. B. bei perimenopausalen Ovarialzysten), ist ihre Wirkung auf den Knochen in verschiedenen Kollektiven unterschiedlich beurteilt worden. Fazit: Die hier vorliegenden physiologischen und klinischen Daten sprechen dafür, dass die Ovulation beim Knochenaufbau und bei der Verminderung von Knochenabbau eine Rolle spielt.

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