Overview of KNDy neurons

Episode 1

The following transcript has been edited for clarity, style, and length.

Mary Jane Minkin, MD: Hello, and welcome to this session of Patient Care Primary View, titled Vasomotor Symptoms and Menopause: KNDy Neurons, Neurokinin Receptors, and Practical Insights.

I’m Mary Jane Minkin, an obstetrician-gynecologist in private practice. I have the privilege of caring for many wonderful women and also serve as a Clinical Professor in the Department of Obstetrics, Gynecology, and Reproductive Sciences at Yale School of Medicine.

One of my special projects at the medical school is running a clinic in the Section of Gynecological Oncology called Sexuality, Intimacy, and Menopause for Cancer Survivors. This clinic reflects my particular interest in menopause, including its unique challenges for cancer survivors.

Today, I’m especially excited to be joined by my good friend, Dr. Lisa Larkin. Lisa was my medical student—a proud moment for me—but she’s also an accomplished physician in her own right. She’s a Fellow of the American College of Physicians, a certified practitioner with the Menopause Society, and the immediate past president of the organization. Lisa, it’s a pleasure to have you here.

Lisa Larkin, MD: Thank you so much, Mary Jane. It’s an honor to join you, and I’m always happy to have these discussions.

I’m Lisa Larkin, a women’s health internist based in Cincinnati, Ohio. I’ve spent half my career in academic medicine, working in the Departments of Internal Medicine and OB-GYN at the University of Cincinnati. My passion is advancing care for midlife women, especially around menopause.

I’m also the founder and CEO of Ms. Medicine, a women’s health company building a national network of clinicians committed to improving midlife healthcare. As Mary Jane mentioned, I’ve been privileged to serve on the Board of Trustees of the Menopause Society for seven years and served as president in 2024. I’m excited to be here today to discuss this fascinating and evolving field.

Minkin: Let’s get started! Today, we’ll focus on vasomotor symptoms (VMS) in menopause and a promising new class of non-hormonal therapies.

We’ll dive into the role of kisspeptin, neurokinin B (NKB), and dynorphin—collectively referred to as "KNDy neurons." Patients often think I’m talking about M&Ms, but no, KNDy neurons are specific neural networks critical to the development of VMS.

We’ll discuss their physiology, the role of neurokinin receptor antagonists in managing symptoms, and their potential benefits beyond hot flashes, such as improving sleep. Lastly, we’ll highlight safety considerations and differences among these emerging therapies.

Lisa let’s start with the basics. Can you explain what KNDy neurons are?

Larkin: Sure. Before diving into KNDy neurons, let me emphasize why this topic is so exciting. We’re in an exciting period for menopausal care. Recent research has significantly improved our understanding of the pathophysiology of hot flashes.

For decades, menopause care was delegated back to OB-GYNs because it was seen as a straightforward issue related to declining estrogen. However, the science now shows it’s far more complex. This deeper understanding has led to targeted drug development, which is really exciting for patients and clinicians.

I like to draw a parallel to the advancements in migraine care. Decades of basic science research into migraine pathophysiology eventually resulted in highly effective, targeted treatments. The same is now happening in menopause care, which is why I’m passionate about engaging my primary care colleagues—internists, family medicine physicians, and others—in this field.

So, KNDy neurons. These neurons reside in the hypothalamus, and they’re at the heart of what causes vasomotor symptoms. While we’ve long known that VMS is triggered by declining estrogen, not all women with low estrogen experience hot flashes. This discrepancy suggested there was more to the story, and that’s where research into the role of KNDy neurons came in.

Minkin: Absolutely. And for years, women were told their symptoms were “all in their head.” I now tell my patients: “Yes, it is in your head—in your hypothalamus, to be precise.” Lisa, can you elaborate on how the hypothalamus contributes to VMS?

Larkin: Of course. The hypothalamus houses the thermoregulatory center, which is critical for maintaining body temperature. KNDy neurons—kisspeptin, neurokinin B (NKB), and dynorphin—are located here and play a pivotal role.

When estrogen levels decline during menopause, these neurons become hyperactive. Specifically, NKB binds to receptors on the KNDy neurons, disrupting the balance and narrowing the thermoregulatory zone. This hyperactivity makes women more sensitive to even slight changes in temperature, leading to hot flashes.

Minkin: And the thermoregulatory center isn’t alone. Right next to it in the hypothalamus is the sleep center, which explains why so many women experience sleep disturbances. Some patients wake up first and then experience a hot flash, while others have a hot flash that wakes them up. Either way, they’re miserable. This overlap is why therapies targeting neurokinin receptors are so promising—they could improve both VMS and sleep.

Larkin: Exactly. And it’s not just about temperature and sleep. The hypothalamus is also essential for reproductive function. The same region involved in VMS is also crucial for regulating luteinizing hormone (LH) and ovulation.

Minkin: That’s an important point. Women with hypothalamic dysfunction, such as hypothalamic amenorrhea, often struggle with infertility because their LH activity is impaired. This region does much more than regulate body temperature—it’s central to reproduction and overall well-being.

This underscores why understanding the hypothalamus and KNDy neurons is so important. It’s not just about improving menopausal symptoms; it’s about recognizing the intricate systems that govern women’s health.