In this episode of The Drive, host Peter Attia interviews Dr. Hanato Tomioka, a specialist at the intersection of reproductive medicine, minimally invasive gynecologic surgery, and gynecologic endocrinology. Tomioka runs a premier fertility clinic in São Paulo, Brazil, and is recognized internationally for his expertise in endometriosis, adenomyosis, and IVF.

The conversation opens with a detailed anatomical and pathophysiological breakdown of endometriosis and adenomyosis — including their shared mechanisms of progesterone resistance, aromatase upregulation, and oncogenic somatic mutations — before moving into diagnosis, where Tomioka explains the shift from surgical laparoscopy toward specialized MRI and transvaginal ultrasound protocols. The discussion of treatment covers hormonal suppression, surgical indications, and the critical mistakes clinicians make in both domains.

The second half pivots to fertility, covering how female age drives chromosomal aneuploidy in a steep nonlinear curve, the role of IVF in women with endometriosis or adenomyosis, egg freezing economics, mitochondrial replacement therapy, and emerging stem-cell-derived oocyte research. Tomioka also references the framework introduced in Nature Reviews by Charles Chapron — the concept of the 'endometriosis life' — as a call to manage the disease chronically rather than episodically.

Endometriosis: Anatomy, Prevalence, and Root Causes

The uterus has three layers: the outer serosa, the muscular myometrium, and the inner endometrium. Endometriosis occurs when endometrial-like tissue grows outside the uterus — on ovaries, fallopian tubes, bowel, bladder, appendix, and even the diaphragm.

Endometriosis affects ~10% of reproductive-aged women (~200 million globally) and is found in 30–50% of infertile women. The relationship is bidirectional: having endometriosis carries roughly a 40% chance of infertility.

Heritability is approximately 50%. Having a first-degree relative with endometriosis confers a 7-times higher risk. Twin studies confirm genetic contribution but incomplete penetrance.

The primary driver is retrograde menstruation — menstrual flow traveling backward through the fallopian tubes into the pelvis. About 90% of women experience this, but only 10% develop endometriosis, suggesting immune dysregulation (macrophage dysfunction) is a necessary co-factor.

"If you look like 200 years ago, a woman back then would have around 100 ovulatory cycles in their lifetime... If you compare that woman to a modern woman, it's about a fourfold increase in this retrograde ovulatory menstruations." — Hanato

Menarche has shifted from ~age 16 to ~age 12; first pregnancy from ~age 20 to 30+; breastfeeding duration and number of pregnancies have both declined dramatically.

This evolutionary mismatch — not anticipated by Darwinian selection — is likely the primary explanation for rising endometriosis prevalence, not just improved diagnosis.

At the molecular level, endometriosis lesions overexpress aromatase (producing their own estrogen), exhibit progesterone receptor downregulation, and carry oncogenic somatic mutations in KRAS and PIK3 kinase in up to 37% of deep infiltrating cases — yet lack metastatic potential due to surrounding fibrosis.

Adenomyosis: The Underdiagnosed Counterpart

Adenomyosis — endometrial-like tissue invading the myometrium — may affect 20–30% of women, making it more prevalent than endometriosis. It was historically called 'internal endometriosis' but is now recognized as a distinct disease with different molecular pathways confirmed by single-cell transcriptomics.

Up to 70% of women with endometriosis also have some degree of adenomyosis, a co-occurrence with major implications for fertility treatment.

The primary mechanism is TIAR (tissue injury and repair): the endometrium breaches the junctional zone — the thin boundary between endometrium and myometrium — and invades the muscle wall. Risk factors include C-section, curettage, miscarriage, and hysteroscopy.

Adenomyosis presents primarily with heavy uterine bleeding (sometimes causing anemia) and painful periods, whereas endometriosis is more associated with the '6 Ds': dysmenorrhea, deep dyspareunia, dyschezia, dysuria, difficulty conceiving, and dysfunctional chronic pelvic pain.

Unlike endometriosis, adenomyosis can only be surgically cured by hysterectomy. For women who still want to conceive, hormonal suppression (GnRH agonists or antagonists for 2–4 months pre-transfer) is the primary intervention, improving implantation rates and reducing miscarriage.

Three Layers of Pain and the Central Sensitization Problem

Endometriosis pain operates on three distinct layers: nociceptive pain (direct tissue injury, responsive to surgery and hormones), neuropathic/nociplastic pain from nerve infiltration (responsive to gabapentin, SNRIs, and nerve-sparing surgery), and central sensitization — rewired pain signaling that persists even after complete surgical clearance.

"Imagine endometriosis lesion is a burglar. Surgery can remove the burglar, hormones can lock the door. But once you have this alarm system ringing and ringing years after years, the wiring changed. And now even a wind can trigger the alarm." — Hanato

Central sensitization requires pelvic floor physiotherapy and pain specialist involvement — not more surgery. Tomioka recommends physiotherapy 8 weeks before surgery to prepare the pelvis, then resuming 2–4 weeks post-operatively.

Diagnosis delay of 5–12 years (6 years in the US, 7 in Brazil) is a primary driver of central sensitization. ACOG published new guidance in early 2025 permitting empirical clinical diagnosis and treatment without requiring surgical confirmation.

Diagnosis: From Surgical Laparoscopy to Specialized Imaging

Diagnostic laparoscopy — the historical gold standard — is no longer recommended as the first-line diagnostic approach. The shift toward non-invasive imaging began approximately 25 years ago.

Three tiers of ultrasound exist: standard transvaginal ultrasound (low sensitivity for endometriosis), augmented ultrasound with the 'sliding sign' (assessing posterior wall adhesions without bowel prep), and the detailed protocol with bowel prep performed by a specialist (sensitivity 95–98%).

"If you do a normal ultrasound and you don't have endometriosis in the report, doesn't mean that you don't have endometriosis." — Hanato

The detailed protocol requires ~1 hour, vaginal gel, and a pre-exam enema to visualize rectal and bowel lesions. It is available at only a few US centers (Mayo Clinic Arizona, Cleveland Clinic).

MRI (non-contrast T1/T2, ~20 minutes) offers 95–98% sensitivity and is the dominant modality in the US. It is superior to ultrasound for extrapelvic lesions (diaphragm, ureter, lateral pelvis) but inferior for bowel endometriosis and lacks the dynamic sliding-sign assessment.

Three endometriosis phenotypes require different imaging strategies: superficial peritoneal lesions (<5mm, often missed by ultrasound), deep infiltrating endometriosis, and endometriomas (ovarian cysts). Tomioka uses both MRI and specialized ultrasound before any surgical planning.

Treatment Decisions: Hormones, Surgery, and the Chronic Disease Framework

Charles Chapron's 'endometriosis life' concept, published in Nature Reviews approximately 7 years before this episode, argues that endometriosis should be managed as a chronic disease — like type 1 or type 2 diabetes — rather than treated episodically. As described in that Endometriosis a high-risk population for major chronic diseases (Nature Reviews concept 'endometriosis life') framework, clinicians must think across the patient's entire reproductive lifespan.

First-line treatment for women not trying to conceive is hormonal: combined oral contraceptives (lowest effective estrogen dose), progestin-only pills (norethindrone, dienogest, desogestrel), or a Mirena IUD (for women without endometriomas, as it does not suppress ovulation).

Surgery is reserved for: inadequate response to hormonal therapy, large endometriomas (>5–6 cm), bowel obstruction risk, ureteral involvement (which can silently cause hydronephrosis and nephrectomy), and appendiceal lesions mimicking neuroendocrine tumors.

Post-surgical Mirena insertion reduces endometriosis recurrence by 88% compared to placebo. Without post-surgical hormonal suppression, recurrence is approximately 10% per year.

NIH invests 15 times more in diabetes research than endometriosis, despite endometriosis costing ~$16,000 per patient per year vs. ~$12,000 for diabetes — a funding disparity that explains the lack of robust clinical trial data.

IVF, Endometriosis, and the Three Biggest Surgical Mistakes

Endometriosis impairs fertility primarily through mechanical disruption — adhesions that compromise fallopian tube function and prevent oocyte pickup or embryo transport — rather than through impaired implantation. Donor egg studies show equivalent implantation rates in uteri with and without endometriosis (the confounding factor is likely undiagnosed adenomyosis).

Mistake #1: Operating on women with central sensitization expecting pain relief. Surgery cannot address rewired central pain pathways — and proceeding without pre-operative physiotherapy preparation leads to poor outcomes.

Mistake #2: Removing endometriomas before egg retrieval. Cystectomy strips adjacent ovarian cortex containing primordial follicles, reducing AMH by 40–50%. The correct sequence is egg retrieval first, then surgical cyst removal if indicated.

Mistake #3: Leaving a hydrosalpinx (damaged, dilated fallopian tube) to preserve the tube. A hydrosalpinx reduces IVF success rates by half through mechanical embryo washout and embryotoxic cytokine secretion. Salpingectomy is supported by Cochrane review evidence.

The Endometriosis Fertility Index (EFI) — scored 0–10 based on tube and fimbrial quality after surgery — predicts natural conception rates post-operatively. A score of 9–10 corresponds to ~65% natural pregnancy rate; low scores indicate direct IVF referral.

Female Age, Aneuploidy, and the Nonlinear Fertility Cliff

Aneuploidy — chromosomal abnormality arising from meiotic errors, 93–95% of which originate from the egg — follows a J-curve by age: slightly elevated in very young women (~20), lowest around age 25, then rising steeply.

Approximate aneuploidy rates by age: 25 (~20–25%), 31–34 (~35%), 35 (~40%), 38 (~60%), 40 (~70%), 42 (~80–85%).

"Reproduction in humans is very inefficient... we are not increasing their quality [with IVF]. We are just grouping, making more embryos." — Hanato

The IVF funnel compounds multiple inefficiencies: ~75% of retrieved oocytes are mature; of fertilized day-1 embryos, only 30–60% reach blastocyst stage (depending on sperm quality and lab); then aneuploidy rate applies on top.

A 40-year-old woman with a typical AMH of ~1 ng/mL might yield ~8 eggs per cycle. After accounting for maturity, fertilization, blastocyst development, and ~70–80% aneuploidy, she may produce only 1–2 euploid embryos per cycle.

Euploid embryo clinical pregnancy rates are relatively similar across ages 30–40, suggesting that once chromosomal normalcy is confirmed, the uterine environment is not the primary limiting factor — quantity of euploid embryos is.

Egg Freezing: Timing, Economics, and the 90% Statistic

Approximately 90% of women who freeze eggs never return to use them — either because they conceive naturally or choose not to use them. This dramatically affects the cost-effectiveness calculation for early freezing.

In Brazil, one egg retrieval cycle costs ~$5,000 USD (one-third medication, one-third procedure, one-third lab/clinic), with annual storage at ~$150. Tomioka considers age 32–35 the sweet spot for cost-effectiveness, despite the biological advantage of freezing at 25.

At age 25, ~75% of retrieved oocytes are mature, and ~80% of day-5 blastocysts would be euploid. With ~15 frozen eggs, estimated live birth probability exceeds 80% for at least one baby.

The median age of social egg freezing patients at Tomioka's clinic is 37–38 — far later than optimal — reflecting both the novelty of the technology and referral patterns toward complex cases.

Tomioka advocates checking AMH and antral follicle count in all women uncertain about their reproductive timeline, noting that antral follicle count varies between follicular and luteal phases and should be rechecked if initially low.

Emerging Technologies: Mitochondrial Therapy, Ovarian Freezing, and Stem Cells

Mitochondrial replacement therapy (MRT) — transferring pronuclei from a parent embryo into an enucleated donor oocyte — addresses mitochondrial DNA disease (37 mitochondrial genes) but does NOT solve age-related aneuploidy, which originates in the nucleus. Two 2024 NEJM papers from Newcastle covered 22 patients with mitochondrial disease.

"It's like a battery swap for the egg, but you're not changing the engine. The engine is the main problem." — Hanato. Clinics marketing MRT as 'egg rejuvenation' for infertility are, in Tomioka's view, misleading patients.

Ovarian cortex cryopreservation — partial oophorectomy at ~30s, with reimplantation into the peritoneum at ~45 — is being explored in the UK to postpone menopause by 10–15+ years. Tomioka notes this is primarily a hormonal intervention, not a fertility one, and that standard HRT is likely simpler and equally effective.

Stem-cell-derived oocytes have been demonstrated in mice with normal phenotypic outcomes. Tomioka estimates clinical application in humans is ~10 years away, citing the complexity of egg production (vs. sperm), unknown epigenetic consequences, and the need for long-term safety data in primates.

HMI-115, a monoclonal antibody targeting the prolactin receptor expressed on endometriosis lesions, is in Phase 3 trials. It may become the first non-hormonal biologic treatment for endometriosis — directly targeting lesion proliferation rather than suppressing ovulation.