Perimenopausal Depression May Signal a Hormonal Component: When to Consider HRT

Women who present in their 40s with new or worsening depressive and anxiety symptoms are not always dealing with straightforward major depressive disorder (MDD), according to Nardin Valentin, DO, ABOM. In many cases, she said, hormonal fluctuation tied to perimenopause or menopause is driving the presentation, and hormone replacement therapy (HRT) deserves a place in the treatment conversation.

Valentin, a general psychiatrist at Virtua Health, has a particular interest in women's mental health and the role of HRT during the perimenopausal and menopausal years, she told Psychiatric Times in an exclusive interview.

Recognizing 'MDD With a Hormonal Component' in Perimenopausal Women

Valentin said the pattern shows up repeatedly in her clinic. Patients between the ages of 40 and 50 present with new-onset anxiety, new mood symptoms, or cognitive fog. Some have a history of depression that had been treated and has since worsened; others have no clear precipitant at all, she explained. When suspicious, Valentin includes queries during the psychiatric intake, she said. In addition to asking if anything has changed recently in the patient's life, she also asks how the patient's menstrual cycle has been behaving. Their answers can often indicate a potential issue.

"Their menstrual cycles are increasing in length, or they're coming more frequently, or they're not coming as frequently, and then they're having a lot of mood variation surrounding their cycle," she said. Patients do not always connect the dots on their own, she added. In these cases, there is often fatigue, anxiety, irritability, and disrupted sleep associated with the cycle changes. At that point, Valentin said the diagnosis might shift. "It's not a clear-cut MDD," she said. "It's more MDD with a hormonal component to it."

The Estrogen 'Delta': Why Hormonal Swings Drive Psychiatric Symptoms

Valentin's working theory centers on variability rather than deficiency. Estradiol levels during perimenopause can swing from undetectable to markedly elevated in the same patient, she said. That range matters, she explained, because estrogen and progesterone receptors are distributed throughout the brain, not just the reproductive system. "Your brain is actually filled with estrogen [and] progesterone receptors," she said.

That framework also shapes how Valentin talks with patients about HRT's safety profile. Newer data have pointed to bone and cardiovascular benefits that contradict earlier findings from the Women's Health Initiative (WHI) study¹, she said. Similarly, a new also suggested a possible protective effect against Alzheimer disease, though she noted the finding is new and runs counter to prior assumptions.²

Especially with these potential benefits, Valentin believes clinicians should have a discussion about HRT with all appropriate patients. "I think every female should have the option of being on HRT," she told Psychiatric Times.

Vasomotor Symptoms, Sleep, and HRT as a Treatment Adjunct

Sleep disruption is often connected to hormonal change to mood symptoms, Valentin said. Vasomotor symptoms (eg, hot flashes and night sweats) are common during this window and directly interfere with sleep, which she called a major contributor to mood and anxiety symptoms generally. When vasomotor symptoms are driving poor or fragmented sleep, she said, "HRT is the most effective treatment for that."

Lab values do not always capture the hormonal variability she is describing, Valentin acknowledged, so a normal panel should not necessarily rule out a potential therapeutic trial. In patients without contraindications who fit the clinical picture, starting HRT alongside appropriate psychiatric treatment is often worth attempting, she added.

Valentin frames HRT as an adjunct rather than a substitute for psychiatric care. "It's not a cure for all, but it's definitely important, if they're having new symptoms or worsening symptoms, to add it as a layer, kind of like an augmentation to treatment,” she said “It's very similar to when we think of if someone has thyroid hormone deficiency, we replete it."

Dr Valentin is a general psychiatrist at Virtua Health in New Jersey.

References

1. Schweitzer K. New Analysis of Women's Health Initiative Data Aims to "Clear the Air" Over Menopausal Hormone Therapy. JAMA. 2025;334(15):1318-1320.

2. Bruno J, Shaw JS, Hosseini SMH; for Alzheimer's Disease Neuroimaging Initiative. Association Between Menopausal Hormone Therapy and Alzheimer Disease Neuropathology. Neurology. 2026;107(5):e218413.