The research, conducted by a team at the University of Health Sciences Prof. Dr. Cemil Tascioglu City Hospital and published in BMC Cancer, examined 138 premenopausal women with non-metastatic, hormone receptor-positive, HER2-positive breast cancer. All of the patients had undergone neoadjuvant therapy — treatment given before surgery — built around anti-HER2 agents, followed by surgical removal of their tumors between 2015 and 2024. The investigators then split the cohort according to whether the women received ovarian function suppression, or OFS, during the adjuvant period, the phase of care that follows surgery and is designed to mop up any remaining cancer cells.

The biology behind the question is straightforward. In premenopausal women, the ovaries are the dominant source of estrogen, the hormone that fuels the growth of hormone receptor-positive tumors. Blocking ovarian output — typically with gonadotropin-releasing hormone agonists that effectively switch the ovaries off — dramatically lowers circulating estrogen. Combined with drugs such as tamoxifen, which blocks estrogen receptors on cancer cells, or aromatase inhibitors, which block estrogen synthesis in peripheral tissues, ovarian suppression is intended to starve any residual disease of its principal growth signal. In HER2-negative disease, landmark trials have shown clear benefits from this strategy. But HER2-positive tumors behave differently, and the arrival of potent anti-HER2 therapies such as trastuzumab has transformed outcomes, raising the possibility that the incremental value of ovarian suppression has shrunk.

That possibility is precisely what the Turkish team set out to test. Of the 138 patients, 60 — or 43.5 percent — received ovarian function suppression as part of their adjuvant endocrine treatment. The remaining 78 did not. The researchers tracked three primary endpoints: disease-free survival, which measures the time before cancer returns anywhere in the body; distant disease-free survival, which focuses specifically on spread to distant organs; and overall survival. They also assessed pathological complete response, abbreviated pCR, as a secondary endpoint. A pCR means that when pathologists examine the tissue removed at surgery, they find no invasive cancer in the breast and no cancer in the sampled lymph nodes — a marker widely regarded as one of the strongest predictors of long-term cure.

The headline numbers were striking in places. Overall, 42 percent of the entire cohort achieved a pathological complete response, a figure that underscores just how powerful neoadjuvant anti-HER2 therapy has become. After a median follow-up of 56 months, 20 patients — 14.5 percent — had experienced a recurrence or developed metastatic disease, and 11 patients, or 8 percent, had died. Those figures, sobering as they are, reflect the reality of a disease subtype that remains challenging even in the modern therapeutic era.

When the investigators compared the two groups, the differences were modest at best. Five-year overall survival was 93.9 percent among women who received ovarian suppression versus 85.8 percent among those who did not — a numerical gap, but one that did not reach statistical significance, with a p-value of 0.4. Disease-free survival was essentially identical between the arms: 80.7 percent with ovarian suppression and 81.3 percent without, yielding a p-value of 0.9. Distant disease-free survival followed the same pattern. In other words, on the primary measures of whether cancer came back or whether patients lived, the addition of ovarian suppression made no statistically detectable difference in this cohort.

The most intriguing signal emerged when the researchers stratified patients by their response to neoadjuvant therapy. Women who achieved a pathological complete response had excellent outcomes regardless of whether their ovaries were subsequently suppressed — their five-year overall survival was a remarkable 100 percent. This finding reinforces a growing consensus in oncology: for patients whose tumors vanish under preoperative anti-HER2 treatment, the prognosis is already so favorable that additional endocrine intensification may contribute little. The residual-disease group told a more nuanced story. Among women who still had detectable cancer at surgery, ovarian suppression was associated with numerically higher overall survival — 89.9 percent versus 77.6 percent — but this apparent advantage did not translate into a disease-free survival benefit, and the difference was not statistically significant.

To account for the possibility that the two groups differed in ways that could confound the comparison — differences in tumor size, nodal involvement, grade, or the type of endocrine therapy received — the team performed multivariate analysis, a statistical technique that adjusts for multiple variables simultaneously. The result was unambiguous: ovarian function suppression showed no independent association with disease-free survival, distant disease-free survival, or overall survival once other factors were taken into account. The authors are careful to note, however, that the study’s statistical power was limited. With 138 patients and relatively few events — 20 recurrences and 11 deaths — the analysis simply cannot exclude a modest benefit that a larger trial might detect.

Another critical caveat concerns the composition of the endocrine therapy itself. The cohort was predominantly treated with tamoxifen, the selective estrogen receptor modulator that has long been the backbone of adjuvant therapy in premenopausal women. Whether ovarian suppression paired with aromatase inhibitors — a more aggressive regimen that eliminates nearly all estrogen production — would perform differently cannot be answered by this dataset. The authors explicitly caution that, given the limited statistical power and the tamoxifen-dominated treatment landscape, their findings should be interpreted with care, and they call for prospective studies to define the role of ovarian suppression in this population with the rigor that only randomized designs can provide.

For clinicians and patients, the practical message is one of individualized decision-making rather than a blanket rule. Ovarian suppression is not a free intervention: it induces a premature, often abrupt menopause, bringing hot flashes, bone density loss, sexual dysfunction, and potential effects on fertility and quality of life. If a young woman achieves a pathological complete response after neoadjuvant anti-HER2 therapy, the data suggest her prognosis is excellent without intensification, and she and her physician may reasonably weigh the burden of suppression against its uncertain benefit. For those with residual disease, the numerically better overall survival observed with suppression — though not statistically significant — may still inform a shared decision, particularly for patients with other high-risk features. What this single-center experience ultimately demonstrates is that the era of effective anti-HER2 therapy has changed the calculus of endocrine intensification, and that the questions guiding treatment for premenopausal, hormone receptor-positive, HER2-positive breast cancer are now as much about avoiding overtreatment as about maximizing it. Larger, prospective trials will be needed to settle the matter definitively, but for now, this study offers a data-driven reminder that more intensive therapy is not always better therapy.

Subject of Research: Ovarian function suppression in adjuvant endocrine therapy for premenopausal hormone receptor-positive, HER2-positive breast cancer after neoadjuvant anti-HER2 therapy

Article Title: The effect of adding ovarian function suppression to adjuvant endocrine therapy in premenopausal patients with hormone receptor-positive, HER2-positive breast cancer who have undergone neoadjuvant therapy: a single-center experience

Article References: Aydin, O., Dogan, H. G. Y., Sonusen, S. D., Erciyestepe, M., Ozturk, A. E., Buyukkuscu, A., Isleyen, Z. S., & Erturk, K. (2026). The effect of adding ovarian function suppression to adjuvant endocrine therapy in premenopausal patients with hormone receptor-positive, HER2-positive breast cancer who have undergone neoadjuvant therapy: a single-center experience. BMC Cancer, 26(1), Article 1140. https://doi.org/10.1186/s12885-026-17017-8

Image Credits: AI Generated

DOI: 10.1186/s12885-026-17017-8

Keywords: breast cancer, HER2-positive, hormone receptor-positive, ovarian function suppression, neoadjuvant therapy, adjuvant endocrine therapy, pathological complete response, disease-free survival, overall survival, tamoxifen, premenopausal, oncology

The study enrolled 952 women aged 18 to 65 years, recruited randomly across four socioeconomic regions of Kerman in 2024. This stratified sampling approach was designed to capture women from different social and economic circumstances rather than relying on a single clinic or neighborhood, which strengthens the representativeness of the findings for the wider urban population. Each participant completed a validated Persian-language version of the Beck Depression Inventory-II, a widely used self-report screening instrument, and a cut-off score above 14 was used to identify women with elevated depressive symptoms. In addition to the psychological assessment, the researchers measured serum levels of four key hormones: progesterone, prolactin, estradiol, and testosterone. Demographic variables including age and body mass index were also recorded, allowing the team to disentangle hormonal effects from other well-known contributors to mood.

The headline result is the sheer scale of the burden. The overall prevalence of elevated depressive symptoms was 40 percent across the sample. When the researchers split the cohort by menopausal status, the figures were remarkably similar: 39 percent of premenopausal women and 41 percent of postmenopausal women screened positive. That narrow gap between the two groups is itself informative. It suggests that the transition through menopause, often assumed to be a period of heightened psychological vulnerability, does not dramatically change the prevalence of depressive symptoms in this population, even though the hormonal milieu shifts profoundly. Postmenopausal women were only slightly more likely to report elevated symptoms than their premenopausal counterparts.

The hormonal findings are where the study becomes technically compelling. In adjusted multivariable logistic regression models, stratified by menopausal status, lower estradiol levels were independently associated with greater odds of depressive symptoms in both groups. Among premenopausal women, the adjusted odds ratio was 0.63, with a 95 percent confidence interval of 0.18 to 0.92 and a p-value of 0.038. Among postmenopausal women, the adjusted odds ratio was 0.61, with a 95 percent confidence interval of 0.23 to 0.88 and a p-value of 0.034. Because these are odds ratios for the hormone variable expressed in a direction where values below one indicate a protective association, the results mean that women with higher estradiol had lower odds of screening positive for depression, and the relationship held after accounting for age, body mass index, and other covariates.

Estradiol is the most potent form of estrogen circulating in the human body, and its influence on the brain extends far beyond the reproductive system. The hormone modulates neurotransmitter systems, including serotonin and dopamine pathways, that are central to mood regulation. It also influences neuroplasticity, cerebral blood flow, and the stress response axis. A long-standing hypothesis in reproductive neuroscience holds that declines or fluctuations in estradiol, whether across the menstrual cycle, after childbirth, or during the menopausal transition, can destabilize mood in susceptible individuals. The new findings align with that framework: in both reproductive stages, women with elevated depressive symptoms had significantly lower estradiol levels than those without, even though the absolute hormone concentrations differ enormously between premenopausal and postmenopausal women.

Equally notable is what did not predict depression. After adjustment, there were no significant associations between progesterone, prolactin, or testosterone and elevated depressive symptoms in either group. Progesterone metabolites interact with inhibitory GABA receptors in the brain and have been implicated in premenstrual mood disorders, while prolactin and testosterone have each been linked to mood in previous research with mixed results. The fact that only estradiol emerged as a significant independent predictor, consistently across both menopausal strata, sharpens the focus on estrogen signaling as the hormonal thread most tightly woven into depressive symptomatology in this cohort. It also underscores the value of measuring multiple hormones simultaneously rather than studying them in isolation, since a single-hormone analysis could easily have produced a misleading picture.

Beyond the hormonal story, the study identified demographic risk factors that echo patterns seen globally. Older age and higher body mass index were independently associated with elevated depressive symptoms in both premenopausal and postmenopausal women. The link between adiposity and depression is well documented in the international literature and is thought to involve chronic low-grade inflammation, insulin resistance, and social and psychological factors related to body image and health status. The age association is consistent with the cumulative burden of life stressors and chronic disease, although cross-sectional data cannot determine whether aging itself, or the conditions that accompany it, drives the relationship. Marital status added a further layer of nuance: divorced or widowed marital status was an additional significant predictor of elevated depressive symptoms in premenopausal women, with an adjusted odds ratio of 1.36, a 95 percent confidence interval of 1.17 to 1.59, and a p-value of 0.043. This association was not reported as significant in the postmenopausal group.

The methodological choices of the study deserve scrutiny. The Beck Depression Inventory-II is a screening tool, not a diagnostic instrument, so the 40 percent figure reflects the prevalence of elevated depressive symptoms rather than clinically confirmed major depressive disorder. Self-report measures can be influenced by somatic symptoms, cultural expression of distress, and response bias, although the Persian-language version used has been validated for Iranian populations. The cross-sectional design is the study’s principal limitation: it captures a single moment in time and cannot establish whether low estradiol causes depression, whether depression alters hormone levels, or whether both are shaped by a common underlying factor. Longitudinal designs, in which hormone trajectories are tracked alongside mood over months or years, would be needed to establish temporal direction. The authors also note that the study was not registered in a clinical trial registry, which is not mandatory for observational cross-sectional designs under current Iranian research regulations, and that the work received no external funding.

Nevertheless, the consistency of the estradiol signal across two very different hormonal contexts is what makes the study worth attention. Premenopausal women experience cyclical estradiol fluctuations at concentrations many times higher than those seen after menopause, yet in both groups the same directional relationship with depressive symptoms appeared after adjustment. This suggests that estradiol’s relevance to mood may operate relative to a woman’s own hormonal baseline rather than at any absolute threshold. For clinicians, the findings hint that reproductive hormonal status could be a meaningful consideration when assessing depression risk in women, alongside established factors such as age, body weight, and social circumstances. For researchers, they set the stage for intervention studies and mechanistic work exploring whether maintaining estradiol within physiological ranges can buffer mood, and for longitudinal cohorts that can finally separate cause from correlation in the intricate dialogue between the ovaries and the brain.

Subject of Research: Prevalence of depression in Iranian premenopausal and postmenopausal women and its association with sex hormone levels

Article Title: Prevalence of depression in Iranian premenopausal and postmenopausal women and its association with sex hormone levels

Article References: Dehesh, T., Mosleh-Shirazi, M. A., & Dehesh, P. (2026). Prevalence of depression in Iranian premenopausal and postmenopausal women and its association with sex hormone levels. BMC Psychology. https://doi.org/10.1186/s40359-026-05692-y

Image Credits: AI Generated

DOI: 10.1186/s40359-026-05692-y

Keywords: Prevalence, depression, Iranian, premenopausal, postmenopausal, women, association, hormone, levels, scientific research