Peter Attia opens with a brief membership pitch for peterattiamd.com, then sets the scene for the conversation ahead. Renato Tomioka is introduced as a clinician whose rare triple expertise — reproductive medicine, minimally invasive gynecologic surgery, and gynecologic endocrinology — positions him uniquely to address some of the most consequential and underrecognized conditions in women's health. Peter previews the arc of the conversation: what endometriosis and adenomyosis actually are and why they are so often missed; how imaging has displaced surgical diagnosis; how hormonal versus surgical decisions change when fertility is on the line; the steep, nonlinear rise in chromosomal abnormalities with age; and what may be coming on the horizon for both treatment and fertility preservation. The framing is urgent — 200 million women affected, a 5–12 year average diagnostic delay, and a fertility landscape most couples do not understand until it is too late.

To understand endometriosis, Tomioka begins with the architecture of the uterus: the outer serosa, the muscular myometrium, and the inner endometrium where embryos implant. Endometriosis, he explains, is a chronic disease in which tissue resembling the endometrium migrates outside the uterus — onto the ovaries, fallopian tubes, bladder, bowel, appendix, and even the diaphragm. The scale is striking: approximately 10% of reproductive-aged women, 200 million globally. ^{[1] — Renato Tomioka "10% of reproductive-age women: Endometriosis affects approximately 10% of reproductive-aged women, equating to roughly 200 million women gl…" 03:48 Play} Among infertile women, 30 to 50% have endometriosis, and the relationship is causal — if a woman has endometriosis, she faces roughly a 40% chance of infertility. ^{[2] — Renato Tomioka "30–50% infertility in endometriosis: Among women struggling with infertility, 30 to 50% have endometriosis, and if a woman has endometriosi…" 04:30 Play} Tomioka notes the strong genetic signal: approximately 50% heritability and a sevenfold elevated risk for women with an affected first-degree relative. The mechanism he considers most important is retrograde menstruation — menstrual blood flowing backward through the fallopian tubes into the pelvis — which occurs in roughly 90% of all women, yet only 10% develop endometriosis, implicating immune dysregulation (particularly macrophage dysfunction) as the difference-maker.

Tomioka draws a striking evolutionary comparison: a woman 200 years ago had menarche at 16, her first pregnancy at 20, breastfed multiple children, and experienced around 100 lifetime ovulatory cycles. A modern woman — menarche at 12, first pregnancy at 30 or later, fewer children, less breastfeeding — may have 400 or more. That fourfold increase in retrograde menstrual events is, in his view, the primary reason endometriosis prevalence is genuinely rising, not just better-detected. ^{[1] — Renato Tomioka "Fourfold increase in ovulatory cycles: Modern women experience roughly four times as many ovulatory cycles as women 200 years ago, likely d…" 09:13 Play} At the molecular level, endometriosis is driven by two interlocking abnormalities: the lesions overexpress aromatase, producing their own estrogen fuel independently of the ovaries, and they are resistant to progesterone, the hormone normally tasked with keeping endometrial tissue in check. This double dysfunction explains why blocking ovarian hormone production is often insufficient. Most striking is Tomioka's observation that up to 37% of deep infiltrating lesions carry somatic oncogenic mutations in KRAS and PIK3CA — giving them cancer's growth machinery — yet fibrosis and adhesions prevent metastasis. He uses a vivid analogy: a 1,000-horsepower Formula 1 engine installed in a golf cart. The power is there; the chassis can't use it.

Tomioka opens this section with a claim that reframes the conversation: adenomyosis is 'the missed disease.' While endometriosis gets most of the attention, adenomyosis — where endometrial-like tissue invades the myometrium — may affect up to 20 to 30% of women, making it potentially two to three times more common. ^{[1] — Renato Tomioka "Adenomyosis prevalence up to 20–30%: Adenomyosis may be even more prevalent than endometriosis, affecting up to 20–30% of women, yet it rem…" 15:46 Play} Though they share molecular features (progesterone resistance, aromatase overexpression, oncogenic mutations), single-cell transcriptomics — citing a paper by Linda Judis — shows they are distinct diseases with different pathways. The mechanism of adenomyosis is described as TIAR (tissue injury and repair): the endometrium breaches the junctional zone, typically after C-section, curettage, or miscarriage, and infiltrates the muscular wall, forming cysts and echogenic buds that enlarge and soften the uterus. Critically, up to 70% of endometriosis patients may have concurrent adenomyosis ^{[2] — Renato Tomioka "Up to 70% of endo patients have adenomyosis: Up to 70% of women with endometriosis may also have some degree of adenomyosis, a comorbidity …" 17:18 Play} — a co-occurrence Tomioka believes has been a hidden confounder in implantation studies. Unlike endometriosis, adenomyosis is definitively cured only by hysterectomy, making fertility preservation a fundamentally different challenge for affected women.

Tomioka frames the typical presentation around the mnemonic of the 6 Ds: dysmenorrhea (period pain so severe that IV medication in the ER is sometimes needed), deep dyspareunia (pain during intercourse at the posterior vaginal wall), dyschezia (pain with bowel movements, especially during menstruation), dysuria (cyclic urinary pain), difficulty conceiving, and dysfunctional chronic pelvic pain lasting more than six months without obvious cycle relation. ^{[1] — Renato Tomioka "Endometriosis presents as a constellation of six types of pain and dysfunction — the six Ds. Each one is often dismissed as normal, and tog…" 21:10 Play} He notes that approximately 10% of endometriosis patients may be entirely asymptomatic, their only clue being unexplained infertility — or, more troublingly, they normalize their pain entirely. Adenomyosis presents differently: heavy uterine bleeding is the hallmark, often accompanied by a painful, enlarged uterus palpable during surgery. Distinguishing the two clinically requires awareness of bleeding patterns (more adenomyosis) versus the pain-dominated constellation (more endometriosis). Uterine fibroids, another common condition causing heavy bleeding and sometimes fertility problems, are introduced briefly as an important differential, classified by their proximity to the endometrial cavity (the submucous types 0–2 being most clinically significant for both bleeding and fertility).

Fibroids are common — present in up to 70 to 80% of women — but mostly asymptomatic. Their clinical importance depends almost entirely on location within the uterine wall. Tomioka walks through the FIGO classification system (0 through 8) in which type 0 fibroids sit entirely within the endometrial cavity and types 1 and 2 progressively extend into the myometrium. These submucous fibroids carry the greatest risk of heavy bleeding and fertility disruption by distorting the implantation surface. Fibroids closer to the outer wall (intramural and subserous) may grow very large yet remain nearly asymptomatic. The key clinical point: a fibroid's location, not its size, determines its impact on both bleeding and fertility.

Pain in endometriosis is not monolithic, and Tomioka argues this is the most underappreciated clinical challenge. The first layer is nociceptive pain — direct signalling from inflamed lesions — and responds well to surgery and hormonal suppression. The second is neuropathic pain from nerve infiltration by deep lesions, causing burning sensations down the legs and back; gabapentin, SNRIs, and nerve-sparing surgery can help. The third and most pernicious layer is nociplastic pain — central sensitization — in which the nervous system has been so chronically activated that it generates pain independently of any active lesion. ^{[1] — Renato Tomioka "Endometriosis pain has three layers: lesion pain, nerve infiltration, and central sensitization. Once the nervous system has been on high a…" 27:40 Play} Tomioka's vivid analogy: surgery removes the burglar and hormones lock the door, but once the alarm system has been ringing for years, the wiring itself has changed. Wind alone can now trigger the alarm. Even a pristine, lesion-free pelvis post-surgery will not stop this kind of pain, which requires multidisciplinary management including pelvic floor physiotherapy and pain specialists. The implication is stark: every year of diagnostic delay compounds the risk of irreversible central sensitization, making early empirical treatment — now sanctioned by ACOG's 2025/2026 guidance — a clinical imperative.

The idea of a typical age of presentation for endometriosis no longer holds: Tomioka reports data suggesting that 50 to 75% of adolescents who present with pelvic pain have endometriosis. ^{[1] — Renato Tomioka "Up to 50–75% of teens with pelvic pain have endo: Among teenagers presenting with pelvic pain, up to 50 to 75% are found to have endometrio…" 29:55 Play} That statistic sits alongside a separate, troubling trend — the possible role of microplastics, pollution, poor diet, and sleep-driven immune dysregulation in genuinely increasing prevalence among younger cohorts. Tomioka is candid that the evidence is not definitive, but the parallel with PCOS (where metabolic factors clearly matter) is suggestive. The diagnostic delay of 5 to 12 years exists for three interlocking reasons: a culture that normalizes and dismisses female pain; the absence of any simple blood biomarker; and the historical requirement for surgical laparoscopy to confirm diagnosis. ^{[2] — Renato Tomioka "5–12 year diagnostic delay: Women with endometriosis wait an average of 5 to 12 years from first symptom to diagnosis, with about 6 years i…" 32:12 Play} This delay is not merely inconvenient — it is medically harmful, allowing central sensitization to develop and the disease to progress. ACOG's 2025/2026 guidance allowing empirical clinical diagnosis is framed as a landmark shift that should reduce the window from first symptom to treatment from years to months.

This chapter is perhaps the most practically important of the episode. Tomioka's central warning is stark: a normal result on a standard transvaginal ultrasound should provide no reassurance to a symptomatic woman. ^{[1] — Renato Tomioka "A standard transvaginal ultrasound can entirely miss endometriosis. The specialized bowel-prep protocol with expert interpretation achieves…" 39:35 Play} The device is the same; the protocol, timing, and operator expertise are what make the difference. The gold standard is a detailed bowel-prep protocol — a simple enema, no-residue diet, and vaginal gel — that takes an hour and in expert hands reaches 95 to 98% sensitivity. ^{[2] — Renato Tomioka "95–98% sensitivity for MRI/ultrasound in endo: Specialized MRI and dedicated endometriosis ultrasound protocols achieve sensitivity of abou…" 36:00 Play} This technique, pioneered in Brazil by radiologists like Luciana Chamier (now at Mass General) and Manoel Orlando, allows visualization of all three endometriosis phenotypes: superficial peritoneal lesions, deep infiltrating disease, and endometriomas. In the US, only a handful of centers — Mayo Clinic, Cleveland Clinic — perform the full protocol; most rely on MRI. Tomioka explains each modality's complementary role: ultrasound provides dynamic assessment (the 'sliding sign' that reveals adhesions) and superior resolution for bowel endometriosis; MRI is better for extrapelvic lesions (diaphragm, ureter, lateral pelvis) and deep nerve infiltration. He almost never operates without the specialized ultrasound. Three tiers of examination are described: standard transvaginal ultrasound (inadequate for endo), augmented ultrasound with the sliding sign technique (a meaningful upgrade), and the full expert bowel-prep protocol (the gold standard).

The first case study grounds the episode's treatment principles in a real clinical scenario. A 20-year-old in pain who wants to preserve fertility but not conceive now faces a structured set of questions: Does she want children? How many? What is her ovarian reserve? What is the disease phenotype — importantly, does she have an endometrioma? How severe is her pain? ^{[1] — Renato Tomioka "Mirena after surgery cuts endo recurrence 88%: Inserting a Mirena IUD after endometriosis surgery reduces recurrence rates by 88% compared …" 52:55 Play} Tomioka explains the logic for each option. Mirena IUD is excellent for five years of progesterone-mediated suppression but does not suppress ovulation, so it cannot control endometriomas, and it is contraindicated if myofascial pain (pelvic floor muscle tension) is present. Combined oral contraceptives are the most common first line, with a preference for the lowest effective estrogen dose to avoid stimulating lesions. Progestin-only pills (norethindrone, dienogest, desogestrel) are an alternative. If she fails to respond at 3 to 6 months, the medication changes or surgery is considered. Surgery is not first-line because it is very likely she will recur within 5 years unless a hormonal agent is used post-operatively — and a Mirena IUD placed after surgery cuts recurrence by 88% vs. placebo. ^{[2] — Renato Tomioka "Without post-surgical hormonal suppression, endometriosis recurs at roughly 10% per year. A Mirena IUD inserted after surgery cuts that rec…" 52:20 Play} The overarching frame is that endometriosis must be treated as a chronic disease requiring a life-plan, not a single intervention.

This pair of cases sharpens the fertility-vs.-symptom dichotomy that runs through the entire episode. For the late-30s woman who has completed her family, first-line medical therapy (combined pill or dienogest/Natazia) provides adequate disease control; surgery is reserved for unresponsive or high-burden disease. [1] The second scenario — a 36-year-old with declining AMH who now wants to conceive — demands a different calculus. Infertility is reframed as a disease of two people: male factor must be excluded via semen analysis, and structural causes assessed by hysterosalpingogram. Tomioka then discusses the Endometriosis Fertility Index (EFI), a surgical scoring system that assigns 0–4 points to tubal, fimbrial, and ovarian quality and predicts natural conception probability post-surgery. An EFI of 9 or 10 gives nearly 65% natural pregnancy rates. A low score — damaged or absent tubes — directs the couple directly to IVF. Crucially, if the tubes are functional, surgery to restore pelvic anatomy may allow natural conception; if not, IVF bypasses the plumbing problem. The episode also clarifies that endometriosis itself likely impairs fertility through mechanical disruption of tubal function, not through impaired implantation — a point supported by donor-egg studies showing similar implantation rates in women with and without endometriosis (with adenomyosis being the probable hidden confounder).

Renato Tomioka shifts the conversation to one of the most underappreciated facts in reproductive medicine: the non-linear rise in chromosomal abnormality with maternal age. ^{[1] — Renato Tomioka "~35% aneuploidy at age 31–34: At ages 31 to 34, approximately one-third of blastocysts are aneuploid; the rate climbs to 40% by 35, 60% by …" 1:02:00 Play} The curve is not what most people imagine — it is J-shaped, with aneuploidy rates actually higher in very young women (around 20, due to monosomy) than at 25, which represents the biological sweet spot. From 25, the rate climbs: roughly 35% at 31 to 34, 40% at 35, 60% at 38, 70% at 40, and more than 80% by 42. Almost all embryo aneuploidy (93 to 95%) originates from maternal meiotic errors, not sperm. Peter visibly reacts to these figures — he had not thought of 31 as a compromised reproductive age. Tomioka reframes IVF: it does not improve egg quality, it simply converts more ovulatory events into observable embryos. A 40-year-old who produces 8 eggs per cycle — typical for that age — will, after the successive filters of maturity, fertilization, blastocyst development, and aneuploidy screening, often be left with zero or one viable embryo to transfer. He also notes an important nuance: once you transfer a euploid embryo, implantation rates are broadly similar across ages 30 to 40, suggesting it is aneuploidy that primarily limits fertility, not other intrinsic egg qualities.

The third case is a 32-year-old with frozen embryos and two failed transfers who arrives without a prior diagnosis of adenomyosis. Tomioka frames this as 'very common.' The mechanism of failure is not implantation per se but pregnancy maintenance: adenomyosis disrupts the junctional zone, triggering uterine contractions that expel the embryo between weeks 6 and 8. ^{[1] — Renato Tomioka "Adenomyosis reduces IVF success by ~30%: Adenomyosis reduces the chances of successful IVF by approximately 30%, with junctional zone invol…" 1:17:00 Play} The fix is not surgical (adenomyomas aside, adenomyosis cannot be excised without a hysterectomy) but hormonal: 2 to 4 months of GnRH agonist treatment (Lupron, goserelin) creating chemical menopause, followed by a frozen embryo transfer using minimal estrogen and high progesterone. Published data show this approach meaningfully improves implantation and live birth rates while reducing miscarriage. ^{[2] — Renato Tomioka "GnRH agonist treatment before embryo transfer: Two to four months of GnRH agonist (e.g., Lupron) therapy before embryo transfer in women wi…" 1:11:35 Play} The distinction between GnRH agonists (which cause an initial flare before downregulating the receptor) and the newer, more expensive oral antagonists (elagolix, relugolix — about $1,000/month) is explained; both work, but agonists have more data and are far cheaper in Brazil. Tomioka also discusses the broader pregnancy risks for women with adenomyosis: preterm birth, preeclampsia, small for gestational age, and elevated C-section rates — and that adenomyosis with junctional zone involvement carries a threefold higher miscarriage risk.

In a brief but pointed section, Tomioka quantifies the research funding imbalance that he sees as the structural root of the diagnostic delay problem. The NIH invests approximately 15 times more on diabetes than endometriosis. ^{[1] — Renato Tomioka "NIH invests 15x more on diabetes than endo: The NIH invests approximately 15 times more money on diabetes research than on endometriosis re…" 1:20:10 Play} Yet the per-patient annual economic burden is higher for endometriosis ($16,000) than diabetes ($12,000), mostly because two-thirds of the endometriosis cost is productivity loss — missed work, missed school, missed careers. Peter asks why, and Tomioka's answer is characteristically direct: the disease has only recently begun to be taken seriously, mirroring the decades-long neglect of menopause research before recent public and clinical momentum. Documentaries, celebrity advocacy, and clinical guideline changes are beginning to shift the landscape.

This case focuses on surgical pitfalls and reveals how even well-intentioned interventions can cause lasting harm. The first mistake is performing surgery on a patient whose primary pain is nociplastic: central sensitization is not responsive to lesion removal, and operating without pelvic floor physiotherapy preparation sets the patient up for disappointment. ^{[1] — Renato Tomioka "Hydrosalpinx halves IVF success rates: A damaged, fluid-filled fallopian tube (hydrosalpinx) reduces IVF success rates by approximately hal…" 1:21:20 Play} The second pitfall is removing endometrioma cysts before egg retrieval. Endometriomas are pseudo-cysts without clean walls — stripping them invariably takes adjacent ovarian cortex where primordial follicles live, reducing AMH by 40 to 50% in published data. ^{[2] — Renato Tomioka "Cystectomy can reduce AMH by 40–50%: Removing endometrioma cysts surgically can reduce ovarian reserve (measured by AMH) by 40 to 50% becau…" 1:19:15 Play} The Fenton reaction (iron-catalyzed hydroxyl radical production inside the cyst) simultaneously destroys follicles from within, making it a double-edged sword. The correct sequence: retrieve eggs first, then decide on surgery. The third mistake is leaving a dilated, damaged fallopian tube (hydrosalpinx) in place. The embryotoxic fluid it drains back into the uterus cuts IVF success rates by approximately half — a finding supported by Cochrane review. Salpingectomy is the standard of care.

This chapter consolidates the episode's core fertility message. Tomioka stresses that maternal age is far more decisive than most clinicians communicate — he has seen doctors encourage 42-year-olds to try naturally after surgery, which he considers a serious mistake given that over 80% of their blastocysts will be aneuploid. ^{[1] — Renato Tomioka "~35% aneuploidy at age 31–34: At ages 31 to 34, approximately one-third of blastocysts are aneuploid; the rate climbs to 40% by 35, 60% by …" 1:02:00 Play} He then reveals the J-curve that few patients or clinicians know about: aneuploidy is actually higher in women under 22 than in women at 25, their biological prime. The sweet spot is around 25, and rates accelerate after 30. The evolutionary interpretation is that selection optimized for 25-year-old mothers. ^{[2] — Renato Tomioka "The aneuploidy rate follows a J-curve, not a straight line. Very young women (under 22) have higher aneuploidy than 25-year-olds due to mon…" 1:23:10 Play} Tomioka also contextualizes IVF's fundamental limitations: it groups embryos together at scale but cannot improve their intrinsic quality. Human reproduction is inherently inefficient — 1,000 eggs lost per cycle to ovulate one — and this inefficiency compounds across every stage of IVF, from retrieval to maturity to fertilization to blastocyst to euploid transfer.

Peter opens with the intuitive argument for freezing eggs at 25 — the biological peak — but Tomioka reframes the question with a striking statistic: approximately 90% of women who freeze eggs globally never return to use them, most because they conceive naturally. ^{[1] — Renato Tomioka "90% of women never use frozen eggs: Only about 10% of women who electively freeze their eggs ever return to use them, raising important que…" 1:24:05 Play} This means the expected value of freezing at 25 is diluted by the high probability the eggs are never needed. The cost-effectiveness calculation therefore shifts the sweet spot to around 32 to 35, when the biological cost of waiting is becoming real but most cycles are still productive. The fertility funnel is then walked through step by step: follicles to mature oocytes (75%), fertilization, blastocyst development (30–60% of day-1 embryos), and aneuploidy screening — each step a multiplier of small numbers. A 25-year-old may start with 15 retrieved eggs and end up with a roughly 80% chance of at least one live birth — which Peter notes still seems surprisingly low. A 40-year-old starting with 8 eggs faces a far grimmer calculation: after the funnel, she may have zero or one euploid embryo. Tomioka personalizes this with the story of a patient who froze at 34, returned at 40, and found a single blastocyst that failed to implant. The cost breakdown in Brazil ($5,000 per cycle, roughly $1,650 per third across medication, procedure, and lab) and Israeli policy (unlimited state-funded IVF) bracket the access discussion.

Peter invites Tomioka to survey the technology horizon for women who want to use their own genetic material at advanced age. Mitochondrial replacement therapy, developed for mitochondrial disease and published in the New England Journal of Medicine by a Newcastle group, transfers nuclear material (pronuclei) into an enucleated donor egg to replace defective mitochondria — but the chromosomes, the actual source of age-related aneuploidy, remain the patient's own. ^{[1] — Renato Tomioka "Mitochondrial replacement therapy swaps the cytoplasm around the nucleus but doesn't fix the chromosomes — the actual source of age-related…" 1:33:40 Play} Tomioka bluntly labels clinics in North Cyprus and Greece selling this as 'egg rejuvenation' as misleading: 'It's a battery swap for the egg, but you're not changing the engine.' Ovarian cortex cryopreservation — freezing a slice of ovarian tissue in one's 30s and reimplanting it at 45 — is theoretically capable of postponing menopause by 10 to 15 years but lacks clinical data and is arguably inferior to standard hormone replacement therapy. ^{[2] — Renato Tomioka "If pluripotent stem cells can be reliably converted into functional, chromosomally normal eggs, age becomes irrelevant to fertility. It has…" 1:36:30 Play} The most transformative technology on the horizon is stem-cell-derived eggs: pluripotent stem cells converted into functional oocytes. It has been demonstrated in mice with normal offspring. Tomioka estimates clinical reality is about 10 years away, at which point age becomes largely irrelevant to fertility. He closes with a nuanced caution about IVF itself: Louise Brown, the first IVF baby, is only 48. Epigenetic effects of fertilization outside the fallopian tube remain uncharacterized, and selection bias makes epidemiological studies hard to interpret.

Looking ahead, Tomioka identifies the ACOG 2025/2026 guidance update as a landmark shift: for the first time, clinicians can diagnose and treat endometriosis empirically based on clinical symptoms, without requiring surgical confirmation. This should dramatically compress the 6-year diagnostic gap — analogous, he suggests, to how statins changed the approach to cardiovascular risk. On the pharmaceutical horizon, HMI-115 is a monoclonal antibody in Phase 3 trials targeting the prolactin receptor on endometriosis lesions. Because endometriosis lesions can express prolactin receptors, this approach may reduce pain and disease progression without the hormonal suppression side effects that dominate current pharmacology. If successful, it would be the first truly biologic, non-hormonal therapy for endometriosis. Tomioka frames both as part of a broader maturation of the field — more awareness, better imaging, new therapeutic options — and returns to the episode's central argument: that the most impactful single intervention is still catching the disease early.

The episode closes with a practical call to action and an emotional coda. Peter frames the takeaway clinically: the single biggest win in endometriosis care is collapsing the diagnostic window from 6 years in the US and 7 in Brazil to 6 months. ^{[1] — Renato Tomioka "5–12 year diagnostic delay: Women with endometriosis wait an average of 5 to 12 years from first symptom to diagnosis, with about 6 years i…" 32:12 Play} Any symptomatic woman — or a partner advocating for one — needs to be assertive: request an MRI, and if warranted, insist on the specialized bowel-prep ultrasound protocol, not accept reassurance from a standard scan. Tomioka then offers the most human moment of the episode. The cases that stay with him longest, he says, are not the most technically demanding surgeries or the most difficult IVF cycles. They are the women who cry during the appointment — not from pain, but from relief. When he tells them: 'You are suffering. I know that's real. It has a name. We have a plan for that.' ^{[2] — Renato Tomioka "The cases that stay with me are not the most complex surgeries, not the difficult IVF cycles. They are those women that cry not from pain, …" 1:56:36 Play} His closing message is direct: if you are suffering and being told your pain is just a normal period, seek a second opinion. The technology exists. The treatment exists. The only thing missing is access to the right diagnosis. Peter thanks Tomioka, and a standard medical-legal disclaimer closes the episode.