Researchers utilise data from Swedish nationwide registers of over 900 000 women
Photo by Sydney Sims on Unsplash
Women affected by premenstrual disorders have a higher risk of perinatal depression compared with those who do not, according to research published March 28th in the open access journal PLOS Medicine. The relationship works both ways: those with perinatal depression are also more likely to develop premenstrual disorders after pregnancy and childbirth. This study suggests that a common mechanism might contribute to the two conditions.
Menstruating women experience cyclical hormone fluctuations through puberty, menstrual cycle, pregnancy and menopause. Some women have difficult to manage symptoms of low mood and depression during these fluctuations. Between a fifth and a third of women are reportedly affected by premenstrual disorders and 11% of mothers suffer perinatal depression – depressive symptoms during pregnancy and up to 12 months after delivery.
Qian Yang and colleagues at the Karolinska Institutet, Sweden and University of Iceland used the Swedish nationwide registers from 2001 to 2018 and identified 84 949 women with perinatal depression and 849 482 unaffected women. The researchers matched the women on age and calendar year, and further controlled for demographic factors, smoking, BMI, parity and history of psychiatric disorders. Among women with perinatal depression, almost 3% had premenstrual disorders before pregnancy compared with 0.6% of matched unaffected women. Women with perinatal depression were also twice as likely to report premenstrual disorders when the menstruation resumed after childbirth, compared to those unaffected by perinatal depression.
The research sheds light on the association between the two conditions and supports a theory that they may share underlying biological mechanisms and/or risk factors. Understanding this association could help healthcare providers to better target support to women most likely to be affected.
The authors add, “This study reveals a strong bidirectional relationship between perinatal depression and premenstrual disorders, using data from over 900 000 pregnancies. The findings suggest that both disorders may exist on a continuum, and emphasise the importance of recognising these susceptibilities in clinical practice.”
Results from a Swedish study of nearly three million women and girls published by The BMJ found that there was no evidence of an increased risk of post-COVID vaccination menstrual changes that were significant enough for healthcare interaction.
The researchers found only weak and inconsistent associations were found between COVID vaccination and contact with healthcare for postmenopausal bleeding. These were even less consistent for menstrual disturbance and premenstrual bleeding.
These findings do not provide any substantial support for a causal association between COVID vaccination and diagnoses related to menstrual or bleeding disorders, say the researchers.
Many women have reported changes to their periods after a COVID vaccination, such as the number of days they bleed and the heaviness of the flow. Self-reporting may capture events that normally would not result in a healthcare contact but may still be sufficiently disturbing to be relevant for the affected women. But calculating the strength of a potential association based on self reports can be unreliable.
To address this, researchers in Sweden drew on high quality health registry data to evaluate the risks of menstrual disturbance and bleeding after COVID vaccination in 2 946 448 women and girls aged 12-74 years from December 2020 to February 2022.
Contact with healthcare included primary care visits, specialist outpatient visits, and days of hospital stay related to menstrual disturbance or bleeding before or after menopause.
Risks were assessed by vaccine (Pfizer-BioNTech, Moderna, or Oxford-AstraZeneca) and dose (unvaccinated and first, second, and third dose) over two time windows (1-7 days, considered the control period, and 8-90 days).
In the main analysis, more than 2.5 million (88%) of women received at least one covid-19 vaccination and over 1.6 million (64%) of vaccinated women received three doses during the study period.
The highest risks for bleeding in postmenopausal women were seen after the third dose in the 1-7 days risk window (28%) and in the 8-90 days risk window (25%).
Adjusting for socioeconomic factors, previous healthcare use, and for several specific medical conditions had only a modest effect on these results.
Analyses of individual vaccines and risk of postmenopausal bleeding suggested a 23-33% increased risk after 8-90 days with Pfizer-BioNTech, and Moderna after the third dose, but a less clear association with Oxford-AstraZeneca.
In premenopausal women, weak associations were found for menstrual disturbance or bleeding after vaccination with any dose (13% or 8% after 1-7 days and 6% or 1% after 8-90 days, respectively). However, adjusting for other factors almost completely removed these weak associations, suggesting that a causal effect is unlikely.
These are observational findings and the authors point to several limitations, including the fact that the time between onset, start of symptoms, and date of healthcare contact might be considerable, making the interpretation of effect of different risk windows challenging.
But this was a large study with near complete follow-up, using mandatory data from nationwide registers.
As such, they say: “We observed weak and inconsistent associations between SARS-CoV-2 vaccination and healthcare contacts for postmenopausal bleeding, and even less consistent for menstrual disturbance, and premenstrual bleeding.”
They add: “These findings do not provide any substantial support for a causal association between SARS-CoV-2 vaccination and healthcare contacts related to menstrual or bleeding disorders.”
A new, safer drug has been developed that could revolutionise the way clinicians treat some of the most common gynaecologic diseases including fibroids and endometriosis. A clinical trial published in the Lancet found that linzagolix, an oral drug that hinders oestrogen production, is an effective and customisable treatment for fibroids. Not only does linzagolix ease symptoms but also shrinks the fibroids themselves.
Professor Hugh S. Taylor, MD, co-author of the paper, said: “No treatments to date for fibroid growth are something I would ever want my patients to take for a prolonged period of time, as they did not treat the underlying cause of the problem. This is an extremely well tolerated class of drugs that can control fibroid growth. We’ve never had anything like that before.”
The suffering and inconvenience caused by uterine fibroids can have a serious impact on quality of life. “This can be an impediment to getting a good night’s sleep and being socially active, and it can even affect job performance,” said Prof Taylor.
As fibroids grow larger, they may begin putting pressure on other organs, resulting in a range of unpleasant symptoms including diarrhoea or constipation and frequent urination. Fibroids can also lead to difficulty in getting pregnant and increased risk of miscarriage. They are more common and aggressive in black patients.
Most drugs commonly used for uterine fibroids, including birth control pills, do not treat the fibroids themselves and just lighten or stop periods. And more aggressive drugs, although they treat the root of the problem are “overkill” Prof Taylor said. For example, leuprolide is an injectable drug that puts patients into a menopausal state by initially overstimulating hormonal receptors, which eventually shuts them down and completely blocks oestrogen production. Although the treatment addresses the fibroids, it also can initially exacerbate symptoms and cause harsh side effects. In more extreme cases, patients may opt for hysterectomy.
Promising clinical trial results
Linzagolix is an oral medication that works similarly to leuprolide by hindering hormone production. However, unlike its predecessor, it works by directly blocking the receptors instead of overstimulating them. The drug is also titratable, allowing reduction of oestrogen production without initiating menopause.
The new drug may however cause menopause symptoms such as hot flashes, with hormonal add-back therapy an option for mitigating these symptoms. For some patients, however, including patients with obesity, hypertension, or diabetes, this therapy has risks and may not be a suitable option. These conditions also tend to be more prevalent in Black patients. In this group, a lower dose of linzagolix without add-back therapy might be preferable.
To test the effectiveness of the drug, Prof Taylor’s team ran two large prospective, randomised, double-blind, placebo-controlled clinical trials known as PRIMROSE 1 and PRIMROSE 2. The studies enrolled patients suffering from substantial bleeding who were randomised to placebo or one of several different doses of the drug: 100mg alone, 100 mg with add-back therapy, 200mg alone, or 200mg with add-back therapy. Patients were followed for one year. The researchers considered the therapy successful if the patient’s bleeding was reduced by half and also stayed in what is considered the normal range.
Patients in all four treatment groups experienced a significant reduction in menstrual bleeding. The 200 mg with add-back therapy group worked with “amazing efficacy,” said Prof Taylor: the clinical trials showed a 75.5% response rate in PRIMROSE 1 and a 93.9% rate in PRIMROSE 2. Even the lower dose of the drug still showed promising results. There were greater than 60% response rates in both trials for the 100mg group with add-back therapy, and the 100mg group without add-back showed better than 50% response rates.
“What is interesting and unique about our trials, that has not been done with other drugs in this class, is that we used a low dose with or without hormones,” said Prof Taylor. “This is a great option for patients who experience severe menopause symptoms from the high dose or have a medical problem where they can’t tolerate hormonal add-back therapy.”
Changing the treatment of gynaecologic disease
Linzagolix is one of several in this new class of drugs in development for the treatment for common gynaecologic diseases. Prof Taylor was also involved in the 2017 clinical trial for elagolix, a medication designed to suppress endometriosis that has recently become available for patients.
Linzagolix has so far been approved in Europe. Taylor says drugs in this class will radically change how clinicians treat fibroids, and he hopes linzagolix will lead to a reduction in future hysterectomies once it becomes available.
“A good medical therapy is finally here for fibroids, and I predict that what was a very common operation will dramatically decrease within the next few years,” he says. “Reducing the need for hysterectomy is very important for patients who don’t want to undergo a major surgery, especially for younger people who may still want to preserve the potential of having children in the future.”
In about 10% of women, endometrium-like tissues (known as lesions) also grow outside of the uterus, leading to endometriosis. Endometriosis is characterised by pain and can cause infertility, but its molecular mechanisms and drivers remain unknown. Now, a comprehensive study reveals how lesions escape immune surveillance, by taking advantage of mechanisms for the body tolerating a foetus during pregnancy.
Definitive diagnosis and clinical response still present significant challenges, with a common treatment being hormonal therapy with surgery. Unfortunately, surgery must be repeated if lesions recur, and they often do. To improve the situation, a better understanding of how and why the lesions grow, their cellular makeup, their microenvironments, and other aspects of their biology is essential.
The Jackson Laboratory’s (JAX) Elise Courtois, PhD, in partnership with UConn Health’s gynaecological surgeon Danielle Luciano, MD, recently completed an important study to develop a comprehensive cell atlas of the disease based on lesions obtained from 14 individuals who had treatment for endometriosis
The paper, published Nature Cell Biology, includes a thorough comparison of healthy endometrium tissue and ectopic (outside their normal site) lesions. The data also describes the endometriosis microenvironment and the conditions that allow the lesions to form and grow in what should be unhospitable regions.
“The study builds a robust foundation for a better understanding of endometriosis and how it grows,” said Dr Luciano. “It’s exciting progress that we hope leads to earlier diagnosis and the ability to specifically target these abnormal cells for better treatments.”
The research team worked with tissues from individuals who had lesion removal at UConn Health for relief of symptoms. All were also receiving hormone therapy, the most frequent endometriosis management strategy. Not surprisingly, given that lesions are described as endometrial-like tissues growing in the wrong place, the cellular composition of the lesions in the peritoneum were quite similar to that of the normal endometrium. On the other hand, ovarian lesions had extensive differences in both composition and gene expression from the peritoneal ones. So while both ovary and peritoneum are receptive to the formation of lesions, they represent different environments and lead to important cellular and molecular differences between the two sites. The finding indicates that site-specific therapeutic design may be necessary to develop more effective treatments.
Another aspect of endometriosis is that, like cancer, the lesions represent abnormal growth that would typically be eliminated by immune surveillance. The researchers therefore investigated the immune cells in the peritoneal lesion microenvironment to see why they do not eliminate the abnormal lesion cells. They found that macrophages and dendritic cells contribute to conditions that promote immune inhibition and the promotion of immunosurveillance escape. Their specific characteristics are similar to those associated with foetal tolerance during pregnancy, which suggests that endometriosis hijacks a necessary, naturally occurring immune process to allow for lesion formation and persistence.
The paper details other aspects of both normal endometrium and ectopic lesions, including properties of vascularisation and the drivers of regeneration in endometrium and, perhaps, the formation of lesions in endometriosis. Of particular interest were key differences in the vascularisation of peritoneal versus ovarian lesions, further emphasising the site-specific nature of endometriosis. Also of note was the identification of a previously uncharacterised population of epithelial cells that may be progenitor cells for both endometrium and lesion formation, but more work is needed to define their precise role.
“Single cell analyses and hyperplexed antibody-based imaging techniques offer powerful insights into the complexity of the endometriosis microenvironment,” said Dr Courtois. “Understanding this complexity will be key for developing the new, efficient diagnostic and therapeutic tools that are so badly needed.”
Overall, the data captures a full description of endometrium and lesions, laying a strong foundation for understanding the vital cellular players and molecular dynamics of the disease. The data represents an important step forward for research into endometriosis and provides essential information for future therapeutics and diagnostics that can provide relief for those with this under-investigated disease.
Adenomyosis, a cause of painful menstrual cramps and heavy bleeding, is more common than generally appreciated, and many hysterectomies could be avoided with alternative treatment, suggests a review of the literature published in JAMA Network.
Adenomyosis is a gynaecologic condition characterised by ectopic endometrial tissue within the uterine myometrium. Up to a third of all women have adenomyosis, which should be considered in the differential diagnosis of abnormal uterine bleeding and/or pelvic pain, the researchers noted. It is considered a common uterine condition, but often goes undiagnosed until it results in a hysterectomy.
However, the findings suggest that surgery may be preventable for some women. The researchers identified a range of medical therapies and uterine-sparing procedures that can alleviate symptoms without resorting to hysterectomy.
“Many women come to me and say the only solution they’ve ever been offered is a hysterectomy. Other low-cost, low-risk options such as medical management or less invasive options have existed for more than 20 years,” said lead author Kimberly A Kho, MD.
Modern ultrasound and MRI imaging, combined with a pelvic examination, can often spot the condition, she added. Dr Kho and colleagues encouraged greater awareness of this condition – along with endometriosis – including among school nurses, who are frequently the first contact for young women who begin menstruating. Society may inaccurately teach women that heavy bleeding and pain during periods are normal, but these symptoms can worsen if left untreated, leading to lower quality of life, pain in sexual intercourse, and fertility problems. “Physicians often consider adenomyosis to be a condition of women in their 40s and 50s because that’s when they have their uteruses removed and receive a diagnosis, but it develops much earlier,” said Dr Kho. “Improved clinical awareness is needed to ensure appropriate patient care and encourage additional studies to improve the understanding of adenomyosis.”
Though there are no FDA-approved therapies specifically indicated for treating adenomyosis, the condition can still be managed by using medications developed for contraception, or for symptoms such as fibroids or endometriosis. The authors noted the need for further research, including what ages and ethnicities are most commonly affected, and what could be learned from the condition about uterine cancers.
A pair of clinical trials showed that combination therapy with relugolix reduced heavy bleeding and pain from uterine fibroids without the risk of side effects from low oestrogen levels.
Relugolix is an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, currently approved for men with advanced prostate cancer. Uterine fibroids are common in women, and a quarter of those who are affected by them experience symptoms such as heavy menstrual bleeding and pain.
Injectable long-acting GnRH agonists are effective treatments for uterine fibroids, but cause BMD loss and thus are not generally eligible for long term use. In the two trials done in North and South America, Africa, and Europe, 71% and 73% of patients, respectively, who received relugolix together with estradiol and norethindrone acetate had significantly lower blood loss, compared with 19% and 15% in the placebo group. Similar bone mineral density (BMD) measures were seen in the placebo and relugolix combination therapy groups; but MD decreased among patients who received relugolix monotherapy.
“For the first time, we have an oral treatment that can effectively and safely improve the symptoms of uterine fibroids, particularly heavy menstrual bleeding,” Ayman Al-Hendy, MD, PhD, of the University of Chicago Medicine, stated in an interview. and added that relugolix may be a viable, long-term alternative to the current surgical treatments available for fibroids patients.
“The goal of this program from the beginning was to develop an effective and long-term treatment as a viable alternative to hysterectomy,” Dr Al-Hendy said. “Any patient with uterine fibroids would be a good candidate for this non-surgical treatment.”
Lauren Schiff, MD, associate professor of minimally invasive gynecologic surgery at the school of medicine at the University of North Carolina at Chapel Hill, said that relugolix seems to be a good option for non-surgical treatment of fibroids.
Dr Schiff, who was not involved with the study, said that understanding bone mineral density (BMD) is key for using relugolix past six months. “If the bone density safety measure is maintained for long-term use, then this would be really ideal medication,” she told MedPage Today.
The trial’s primary endpoint was less than 80 ml blood loss, and >50% reduction in total blood loss from trial start. The investigators assessed several secondary outcomes, including amenorrhea, volume of menstrual blood loss, distress, pain, anaemia, fibroid volume, and uterine volume.
Around 388 participants were randomised in the first trial, and 382 in the second.
Around three-quarters of patients who received relugolix combination therapy reached the primary endpoint, with the treatment effects appearing similar baseline characteristics.
Amenorrhea over the last 35 days of the trial occurred in 52% and 50% of participants who received relugolix combination therapy in each trial, respectively. Pain was also reduced in the treatment groups.
Patients who received the combination therapy also had improvements in pain, distress from bleeding and pelvic discomfort, anaemia, and experienced reduced uterine volume. However, significant shrinkage in fibroid volume was not observed.
The prevalence of side effects was similar in the relugolix combination therapy group and the placebo cohort, with hot flashes being the most commonly reported side effect in the trial.
Strict assessment criteria for patients meant generalisability was limited. Additionally, study duration was only six months. The researchers plan to release data from a 28-week extension study, as well as a 52-week randomised-withdrawal trial, and these may shed more light on safety and efficacy in the long term.
Journal information: Al-Hendy A, et al “Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy” N Engl Med 2021; DOI: 10.1056/NEJMoa2008283.
