Anti-inflammatory steroid could reduce heavy menstrual bleeding


Women who experience heavy menstrual bleeding could have their blood loss reduced by treatment with a common anti-inflammatory steroid, research suggests.

The study could pave the way for dexamethasone to be used as a safe, effective therapy – the first new class of treatment for heavy menstrual bleeding in nearly 20 years.

It is the first time an anti-inflammatory steroid has been trialed to treat this common health problem, which affects around one in four women in the UK and can persist for years.

The most commonly used treatment for reducing menstrual bleeding – a hormone-releasing device that is inserted into the womb cavity – is highly effective. However, nearly one fifth of new users are dissatisfied with the side effects, which include unpredictable bleeding. It is also unsuitable for women who are trying to get pregnant.

Treatment option

The trial – undertaken by a team from the University of Edinburgh – involved 107 women aged between 21 and 54 years old who had experienced heavy menstrual bleeding for time spans ranging from six months to 37 years.

The study found that women who were given a 0.9 mg dose of dexamethasone twice daily for five days showed an average reduction in menstrual blood loss volume of 19 percent.

Researchers say the findings mean dexamethasone could be a future treatment option for women whose heavy menstrual bleeding harms their quality of life or health. It could also be used by women who experience unacceptable side-effects with hormonal treatment but do not want surgical treatment, and those who wish to try for pregnancy.

Taboo topics

Menstruation and heavy menstrual bleeding are still taboo topics and the debilitating impact of the latter is under-reported by patients. Our findings open the way for further study of dexamethasone as a possible safe and effective therapy,” says Hilary Critchley,
professor of reproductive medicine at the University’s MRC Centre for Reproductive Health.

“This trial evolved from groundbreaking laboratory research and years of multi-disciplinary collaboration between clinicians and methodologists, combined with specialist expertise in new efficient and ethical approaches to trial design. It has been an exciting and gratifying journey,” says Dr. Pamela Warner, reader in medical statistics at the University’s Usher Institute.

The symptom of heavy menstrual bleeding (HMB) affects 20% to 52% of menstruating UK women [1], [2], [3], [4], and in developing countries is 4 to 27%, or more in older (multiparous) women [5]. HMB diminishes quality-of-life and has adverse impact on employment and family/caring roles [6], [7], [8].

In otherwise healthy mid-age women, the morbidity due to HMB is often underestimated, whereas the cumulative impact on quality of life (QOL), over 30 days per year, would be unacceptable in most other health conditions [7,9]. Menstruation is acknowledged globally as incurring costs that exacerbate poverty. Hence some recent government initiatives to encourage/fund provision of free menstrual protection [7,10].

Current management of symptom of HMB is generic and includes conservative, medical or surgical approaches (endometrial ablation and hysterectomy). There are diverse potential mechanisms for HMB [8,11], so identifying an effective treatment often has to be trial-and-error [8,9,12].

In routine clinical practice, particularly primary care, first line treatment is usually medical therapy (hormonal or non-hormonal) but this may be found to be ineffective, or may not be tolerated, for example on account of common side effects of hormonal treatments [6,9,12]. In the UK NHS HMB Audit (2012–2013) of hospital gynaecology clinic healthcare (n = 8183) it was reported that oral medication, LNG-IUS and surgery were received within the follow-up year by 29%, 33% and 43%, respectively, of patients newly attending hospital outpatient gynaecology clinics, while 18% received no treatment [13].

No novel medical treatment for HMB has been developed for near 20 years, no time-specific (non-hormonal) treatment for at least 30 years. An established highly effective treatment for HMB is the contraceptive levonorgestrel-releasing intrauterine system (LNG-IUS; available since 1995, licensed for HMB in 2001) [3,6,9,12]. However, the LNG-IUS is unsuitable for women desiring pregnancy (as are systemic progestin therapies) and 17% of women receiving LNG-IUS for HMB were dissatisfied with this treatment [3].

A 2013 systematic review of non-surgical treatments for HMB found that trials of non-hormonal medical treatments for HMB were completed in the main over two decades ago, before 1996, and generally imposed an entry criterion of objectively assessed average baseline menstrual blood loss volume (MBL) exceeding 80 mL [12]. The medical treatments reviewed showed good percent reductions in measured MBL volumes, for treatment compared to baseline or placebo (26% to 54% reduction for anti-fibrinolytics, 20% to 52% for NSAIDs) [12]. However, when prescribed for HMB in routine clinical practice, patients very often report these treatments as being or soon becoming insufficiently effective [6,9].

The 2012 UK NHS HMB Audit found that at one year after index attendance at gynaecology clinic, over a third of women (36%) were ‘unhappy’ or ‘very unhappy’ with their ongoing HMB symptoms [13]. Furthermore, by this point there had been a switch to different treatment (possibly surgical), by over half those starting with oral medication, and by one third starting with IUS [13].

Alternative treatment options for HMB are needed for surgical intervention to be avoided and fertility/ uterus preserved. This highlights the urgent need for targeted medical treatment for the debilitating symptom of HMB, that is effective, that does not have unacceptable side effects, and that can be used longish-term, even while seeking to become pregnant.

Endogenous glucocorticoids inhibit angiogenesis [14]. Regulation of endometrial blood vessel function is required to limit endometrial bleeding and menstrual blood loss [15]. Local endometrial glucocorticoid deficiency may, therefore, result in increased menstrual blood loss. We have demonstrated that endometrium from women with HMB has increased luteal phase expression of 11βhydroxysteroid dehydrogenase type 2 (11βHSD2), an enzyme which inactivates cortisol (the major glucocorticoid) [14].

We thus hypothesised that “rescue” of luteal phase endometrial glucocorticoid deficiency, at an early stage of endometrial repair/angiogenesis, would improve endometrial (spiral arteriole) blood vessel differentiation, augment local blood vessel vasoconstriction at onset of menses, and reduce volume of menstrual bleeding [14], [15], [16]. Dexamethasone was selected for use because it is not inactivated by 11βHSD2, but converted to 11-dehydro-Dex which remains bioactive.

We then conducted a small “proof of concept” animal study, which provided highly supportive evidence for reduction in volume of menstrual bleeding with dexamethasone (a cortisol surrogate/ glucocorticoid receptor agonist), administered in the luteal phase several days prior to expected menses. (see Supplement A)

This dose-finding study aimed to determine (i) if dexamethasone administered to women seeking treatment for the symptom of HMB is safe, acceptable and efficacious, and (ii) the optimal dose from those tested. A Bayesian adaptive trial was designed, requiring participation of substantially fewer women than a traditional multi-arm randomised trial [16,17].

reference link:

More information: Pamela Warner et al, Low dose dexamethasone as treatment for women with heavy menstrual bleeding: A response-adaptive randomised placebo-controlled dose-finding parallel group trial (DexFEM), EBioMedicine (2021). DOI: 10.1016/j.ebiom.2021.103434


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