Male vs. Female Brain Differences & How They Arise From Genes & Hormones | Dr. Nirao Shah

Andrew Huberman

Jul 28, 2025

Episode description

My guest is Dr. Nirao Shah, MD, PhD, a professor of psychiatry, behavioral sciences and neurobiology at Stanford University School of Medicine. We discuss how the brains of males and females differ and how those differences arise from different genes and hormones during fetal development, in childhood and adulthood. We discuss what drives male- versus female-specific behaviors and how hormonal fluctuations across the lifespan, including puberty, the menstrual cycle, menopause and aging – affect behavior, cognition and health. Additionally, we discuss how biology relates to gender identity and the impact of hormone therapies on brain circuits that regulate mating, parenting and social bonding.

Episode show notes: https://go.hubermanlab.com/rJuyFMY

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*Dr. Nirao Shah*
Stanford lab website: https://med.stanford.edu/nirao.html
Stanford academic profile: https://med.stanford.edu/profiles/nirao-shah
Publications: https://med.stanford.edu/profiles/nirao-shah#publications
X: https://x.com/shah_laboratory

*Timestamps*
00:00:00 Nirao Shah
00:02:11 Mice, Humans & Brain, Biological Conservation
00:05:25 Hormones, Nature vs Nurture
00:07:13 Biological Sex Differences, Chromosomes & SRY Gene, Hormones
00:16:01 Sponsors: Maui Nui & Eight Sleep
00:19:09 Androgen Mutations, Feminization & Masculinization
00:22:04 SRY Gene; Animals & Sexual Trans-Differentiation
00:27:49 Hormones & Biological Brain Differentiation
00:31:22 Congenital Adrenal Hyperplasia, Androstenedione; Stress & Pregnancy
00:35:56 Genes, Brain Differentiation & Sexual Identity; Congenital Adrenal Hyperplasia
00:43:37 Testosterone, Estrogen & Brain Circuits
00:47:27 Sponsors: AG1 & LMNT
00:50:36 Intersex Individuals, Castration
00:52:23 Female Sexual Behavior, Brain, Testosterone & Pheromones
00:57:58 Identify as Heterosexual or Homosexual, Difference in Hormone Levels?
01:00:42 Gender, Sexual Orientation & Hormones; Hormone Replacement Therapy
01:10:21 Aromatization; Steroid Hormones & Gene Expression
01:15:00 Kids & Changing Gender Identity
01:19:05 Sexual Behavior, Refractory Period & Male Brain, Tacr1 Cells
01:21:31 Sponsor: Function
01:23:19 Hypothalamus, Dopamine, Prolactin, Cabergoline, Libido, Dopamine
01:27:05 Brain Circuits, Aggression & Sexual Behavior
01:32:40 Refractory Period; Age, Testosterone & Libido
01:36:07 Tacr1 Cells in Females, Periaqueductal Gray & Innate Behaviors
01:40:00 Parenting Behaviors & Brain Circuits; Pet Dogs
01:43:12 Oxytocin, Pair Bonding, Vasopressin; Biological Redundancy
01:47:22 Libido, Melanocortin, Tacr1 Neurons; GLP-1 Agonists, Clinical Trials; Kisspeptin
01:56:43 Female Brain Changes, Menstrual Cycle, Pregnancy, Menopause; Estrogen; Men & Hormone Fluctuation?
02:04:10 Life Experience Male vs Female, Sex Recognition, Behaviors & Context
02:16:05 Pain Management; Endocrine Disrupters, Gender Identity
02:21:03 Future Projects
02:24:29 Zero-Cost Support, YouTube, Spotify & Apple Follow & Reviews, Sponsors, YouTube Feedback, Protocols Book, Social Media, Neural Network Newsletter

Disclaimer & Disclosures: https://www.hubermanlab.com/disclaimer

Mindsip insights from this episode:

Understand estrogen's role in masculinizing the male brain

In the male brain, testosterone is converted into estrogen by an enzyme called aromatase, and it is this estrogen that is primarily responsible for masculinizing brain circuits.

#estrogen

#neurology

Activate latent opposite-sex circuits with testosterone in female brains

Adult female mice given testosterone will display male sexual behaviors, indicating the underlying neural circuit exists but is normally inactive due to the absence of the hormone.

#neurology

#testosterone

Recognize irreversible sex-specific brain circuits from early hormones

Early life hormones cause irreversible, sex-specific cell death in the brain, meaning males and females permanently lose different sets of neurons that cannot be recovered in adulthood.

#hormones

#neurology

Understand femaleness as a default genetic pathway

Unlike the SRY gene for maleness, no single gene has been identified in mammals that determines femaleness; it appears to be the genetically programmed default pathway in the absence of SRY.

#genetics

Activate neurons to eliminate post-ejaculatory refractory period

Activating a small population of about 2,500 neurons in the male mouse hypothalamus can reduce the post-ejaculatory refractory period from several days to a single second.

#hypothalamus

#neurology

Understand 'penis at 12' syndrome and its genetic implications

A rare genetic condition where individuals lack the enzyme to convert testosterone to the more potent DHT causes them to be born appearing female, only to spontaneously grow a penis at puberty.

#genetics

#testosterone

Understand SRY gene's role in determining biological maleness

The presence of a single gene, SRY, not the entire Y chromosome, is the primary biological determinant of maleness, and its absence results in the default female developmental pathway.

#genetics

Understand cyclical rewiring of female brain for enhanced cognition

In adult female rodents, some neural pathways can dramatically change, showing a threefold increase or decrease in connectivity every five days in sync with the ovulatory cycle.

#cognition

#menstrual-cycle

Reevaluate oxytocin's role in monogamous behavior

Contrary to popular belief, prairie voles genetically engineered to lack oxytocin receptors still form monogamous pair bonds, suggesting oxytocin is not essential for this behavior.