Endometrial vascular changes and bleeding disturbances with long-acting progestins
Introduction
Disturbances of the menstrual bleeding pattern are an inevitable consequence of use of long-acting progestogen-only contraceptive methods [1]. These disturbances may range from amenorrhea, irregular and unpredictable spotting or light bleeding [2] to episodes of prolonged and frequent bleeding or spotting [3], [4]. Heavy bleeding is rare, although prolonged episodes of light bleeding may occasionally add up to a greater volume of total blood loss per month than the woman may have experienced in her normal menstrual cycles [5]. The great majority of women using these methods experience bleeding that is lighter in volume than their usual cycles. Nevertheless, a minority of women experience unpredictable, inconvenient bleeding of sufficient degree that they discontinue use of this method. Discontinuation rates vary greatly between methods and ethnic groups, and are greatly influenced by pretreatment counseling [1].
The mechanisms underlying these disturbances are still poorly understood; a better understanding of the mechanisms ought to help in the development of techniques to treat or prevent the unpredictable bleeding. Over the past 20 years, there has been a gradually escalating research effort to study all aspects of this clinical problem. A series of important publications by the World Health Organization and the National Institutes of Health describe the research [6], [7], [8], [9], [10].
This research has confirmed that activity and expression of a number of molecular systems are altered in endometrium exposed to long-acting progestogen-only methods, although it is far from clear how the changes in these systems link together. Some of these changes could lead to a loss of integrity in parts of the tissue or an increase in fragility of epithelium or vessels [11].
It has been known for many years that abnormal vessels may develop in the endometria of women exposed to contraceptive steroids, whether oral or injected [12]; however, only recently have researchers begun to fully comprehend the structural and functional changes of endometrial microvessels in women exposed to progestogens [13], [14].
Section snippets
Endometrial histology and vascular morphology
Continuous progestogen exposure in the presence of variable amounts of endogenous ovarian estradiol secretion leads to a wide variety of endometrial histological appearances; these range from apparent complete atrophy to ‘suppressed secretion’ to typical secretory changes, and sometimes even typical proliferative phase appearances [15]. The classical changes of prolonged progestogen exposure are of marked stromal decidualization with suppression of surface and glandular epithelium. With
Hysteroscopic studies of endometrial vessels
Studies of biopsy tissue give limited information about the appearance and function of endometrial vessels in vivo; however, direct hysteroscopic inspection has the potential to provide a completely different dimension on superficial vascular changes in relation to disturbances of bleeding with progestogens. We have conducted a series of hysteroscopic studies on women using Norplant for contraception. These difficult studies were all carried out with office hysteroscopy using low pressure
Endometrial surface vascularization and vascular patterns
Surface vascularization was defined as the area of endometrial surface covered by relatively distended small vessels. This showed a patchy distribution in Norplant users, but vascular appearances were relatively uniform in those with dysfunctional uterine bleeding [29]. The area of obvious vascularization was significantly greater in Norplant users than in those with DUB. The area of vascularization in Norplant users correlated significantly with the number of days of breakthrough bleeding in
Vascular fragility
There is now substantial direct and indirect evidence to support the hypothesis of increased vascular fragility in some small vessels near the surface of endometria exposed to long-term progestogens Fig. 1a, Fig. 1b, Fig. 1c. This may result in spontaneous petechiae and ecchymoses (Fig. 2). In order for frank bleeding to occur, there must also be increased fragility of the attachments of the superficial endometrial epithelium. This may lead to the appearance of patchy shedding of the
Conclusions
There is now clear evidence to confirm the presence of abnormal superficial microvessels within the endometria of women exposed to long-acting progestogens. It is a safe assumption that these abnormal and fragile vessels are in some way linked to the troublesome symptom of breakthrough bleeding that occurs in many women using these agents. The molecular disturbances underlying this abnormal angiogenesis and abnormal vascular fragility are still unclear. Until now, the only treatment that
Acknowledgements
The hysteroscopic and endometrial biopsy studies of Norplant users were sponsored by Population Council, New York.
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Effects of doxycycline on serum and endometrial levels of MMP-2, MMP-9 and TIMP-1 in women using a levonorgestrel-releasing subcutaneous implant
2009, ContraceptionCitation Excerpt :Various mechanisms have been implicated in the occurrence of the irregular ESB: increase in microvascular density due to endometrial tissue atrophy [14,15], decreased expression of thromboplastin and endothelin [14] and increased endometrial vascular fragility [16,17]. Matrix metalloproteinases (MMPs) have been associated with abnormal endometrial bleeding [12,18–20]. MMPs are a family of zinc-dependent proteases that degrade specific components of extracellular matrixes (ECMs) [21].
Effects of progesterone, levonorgestrel and medroxyprogesterone acetate on apoptosis in human endometrial endothelial cells
2009, ContraceptionCitation Excerpt :Endometrial angiogenic factors, metalloproteinases and tissue factor have been hypothesized to alter capillary vessel integrity and result in the abnormal endometrial spotting and bleeding and spotting/bleeding (S/B) in women using progestin-only contraceptives [1–3].
Effects of ethinyl estradiol and ibuprofen compared to placebo on endometrial bleeding, cervical mucus and the postcoital test in levonorgestrel subcutaneous implant users
2008, ContraceptionCitation Excerpt :The nature of the bleeding problem associated with progestin-only contraceptives is such that it is perceived as relatively unimportant by the physician but is significant for the consumer, resulting in premature discontinuation of the method [3,7]. The primary reason for discontinuation of progestational contraception is the high incidence of irregular, frequent and sometimes prolonged vaginal S/B [1,13]. This appears due to the fact that the incidence, frequency and duration of this side effect improves (becomes less) with the increased duration of LNG SI use [13].
A randomized, controlled trial of asoprisnil, a novel selective progesterone receptor modulator, in women with uterine leiomyomata
2007, Fertility and SterilityCitation Excerpt :Management of leiomyoma-related bleeding with GnRH-a typically does not result in amenorrhea for 60–90 days after the commencement of therapy (22–24). On the other hand, high-dose progestin treatments are often associated with breakthrough bleeding and spotting that result from the direct effects of progestins on the endometrium and are problematic for patients who complain of HUB as the reason for seeking medical care (25). Although the exact mechanism of asoprisnil-induced amenorrhea is still not completely understood, several lines of evidence strongly suggest that asoprisnil controls uterine bleeding predominantly via a local, endometrium-specific, PR-mediated effect (18).
Endometrial effects of intrauterine levonorgestrel
2007, Contraception
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Present address: Department of Obstetrics and Gynaecology, Imperial College at St Marys Hospital, Norfolk Place, London W2 1PG.