Elizabeth A. Stewart

Uterine leiomyomas are common noncancerous hormonally-dependent neoplasms comprised of uterine smooth-muscle cells and fibroblasts. Despite their significant impact on morbidity, effective non-hormonal medical treatments are lacking. In vitro studies have identified the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway as a promising target in leiomyoma cells. Our objective was to evaluate the efficacy of AZD1480, a JAK 1/2 inhibitor, in treating uterine leiomyomas using a patient-derived xenograft murine model. Ovariectomized immunodeficient mice received an estrogen and progesterone pellet and were subsequently implanted with human leiomyoma tissue surgically resected from premenopausal women not on hormonal medication. Mice were divided into treatment (n = 6) and vehicle control (n = 6) groups receiving either 50 mg/kg of AZD1480 or vehicle via oral gavage for 5 days/week for 28 days. Our results demonstrate a significant AZD1480-mediated reduction in both xenograft volume (59.5% vs. 0.3%; treated vs. control, p < .0001) and weight (56.0% vs. 31.2%; p = 0.03) compared to controls. Moreover, xenografts from the treated group exhibited a significant decrease in cell density(p = 0.01). Levels of pSTAT3-positive cells (4.1% vs. 10.3%), Ki67-positive cells (4.1% vs. 6.5%), and fibrillar collagen (19.8% vs. 29.5%) declined but did not reach statistical significance, whereas AZD1480 treatment significantly reduced blood vessel formation in the xenografts (20.1 vs 45.6 per FOV; p = 0.01). These findings suggest JAK inhibition as a potential treatment for uterine leiomyomas by targeting angiogenesis. However, further studies are warranted to explore alternative JAK inhibitors, examine downstream effects, optimize dosing, and establish clinical efficacy and safety.

To examine the risks of long-term de novo psychiatric disease in women with primary infertiltiy compared to age-matched referrent women. Retrospective, population-based cohort of 1,001 women with primary infertility and 1,001 age-matched (± 1 year) referent women aged 18–50. The “index date” was date of first clinical note for infertility and included visits fromJanuary 1, 1980 to December 31, 1999. Baseline characteristics were collected by chart review. Outcome data was evaluated through December 31, 2020. Primary outcomes were baseline prevalence and de novo rates of subsequent psychiatric disorders including depression, anxiety, bipolar disorder, substance abuse, suicidality, and somatization evaluated by Cox proportional hazards modeling. Among women with primary infertility and referent women, the median duration of follow-up was 23.7 years. The risk of de novo psychiatric disorders was not significantly different between groups. Additionally, the risk of de novo psychiatric disorders did not significantly differ between those with isolated male factor versus isolated female factor infertility. Among women with primary infertility, the cumulative incidence of de novo depression and anxiety was significantly higher among women diagnosed with primary infertility in the 1990s compared to the 1980s. Women with primary infertility, in a historical population-based cohort, do not have a significantly different long-term risk of de novo psychiatric diagnoses compared to age-matched referent women. Our findings support the notion that infertility diagnosis and treatment present an acute period of stress and for some psychologic distress, neither of which persist or increase the risk for development of future psychiatric disease.

Survey data from the Mayo Clinic Breast Disease Registry were used to assess fertility counseling and fertility preservation strategies in a modern cohort of young women with breast cancer. One hundred respondents were identified who were under age 50 at the time of breast cancer diagnosis and who expressed interest in future childbearing near the time of diagnosis and/or 1 year later. Ninety-three percent of the 81 respondents to the year one survey recalled fertility counseling prior to cancer treatment. Most who reported a high level of fertility concern declared that this concern had impacted their treatment decisions, often shortening their planned duration of endocrine therapy. Approximately half had taken steps to preserve future fertility, and a third had used a gonadotropin-releasing hormone agonist either alone or combined with another method (e.g., embryo or oocyte cryopreservation).

Purpose of review: Uterine fibroids is a common problem in reproductive-age individuals, frequently causing abnormal uterine bleeding, bulk symptoms, and adverse reproductive outcomes. Traditionally, almost half of the women with symptomatic fibroids received surgery for definitive treatment. There are a growing number of nonsurgical options for treatment that have become available for patients who desire conservative treatment or those with contraindications to surgery. Recent findings: The introduction of oral gonadotropin-releasing hormone antagonists in combination with low-dose physiologic hormonal therapy demonstrated improvement in heavy menstrual bleeding, pain, and quality of life with preservation of bone density and a modest reduction in uterine volume with few hypogonadal side effects. Magnetic resonance-guided focused ultrasound surgery and uterine artery embolization continue to be minimally invasive procedural alternatives to hysterectomy that are safe and effective. Summary: As more options for conservative management of uterine fibroids became available, it is important to counsel patients on possible options based on the size, location, and number of the fibroids as well as severity of the symptoms, plans for pregnancy, how close they are to menopause and their treatment goals.

Uterine leiomyomas are common hormone-responsive neoplasms that frequently cause heavy menstrual bleeding, anemia, pelvic pressure, pain, and adverse reproductive outcomes. In this overview, the efficacy and safety of oral gonadotropin-releasing hormone (GnRH) antagonists, co-administered with menopausal replacement-level steroid hormones or used at doses to avoid complete hypothalamic suppression, are reviewed for the management of uterine leiomyomas. Oral GnRH antagonists provide rapid suppression of sex steroids and avoid the initial steroidal flare and resultant temporary worsening of symptoms typically seen with parenteral GnRH agonists. Oral GnRH antagonists are effective in reducing leiomyoma-associated heavy menstrual bleeding, with high rates of amenorrhea and improved anemia and leiomyoma-associated pain, and providing modest reduction in uterine volume when used in combination with menopausal replacement-level steroid hormones. This add-back therapy can reduce hypogonadal side effects, including hot flushes and bone mineral density loss, close to levels seen with placebo therapy. Currently, both elagolix 300 mg twice daily with once-daily estradiol (1 mg) and norethindrone (0.5 mg) and relugolix 40 mg once daily with estradiol (1 mg) and norethindrone (0.5 mg) combination therapy are approved for leiomyoma treatment by the U.S. Food and Drug Administration. Linzagolix is under investigation in the United States but approved at two does with and without steroid hormones in the European Union. The efficacy of these agents appears to be robust over a wide spectrum of clinical presentations, demonstrating that worse disease parameters at baseline do not appear to inhibit efficacy. Across clinical trials, participants largely reflected the population of individuals affected by uterine leiomyomas.