Peter Attia MD397 - Endometriosis and adenomyosis: diagnosis, fertility, reproductive aging, & emerging treatments
CHAPTERS
- 0:01 – 3:43
What Endometriosis Is and How Common It Is
Dr. Tomioka explains the three layers of the uterus and defines endometriosis as endometrial-like tissue growing outside the uterus. He gives prevalence figures and the link to infertility.
- •Uterine layers: serosa, myometrium and endometrium
- •Endometrial-like tissue can sit on tubes, ovaries, bowel, bladder, appendix and diaphragm
- •About 10% of reproductive-age women (around 200 million) have it
- •30–50% of infertile women have endometriosis, and about 40% of women with endometriosis are infertile
- 3:43 – 9:02
Risk Factors and the Retrograde Menstruation Theory
The discussion covers heritability and possible environmental triggers, then focuses on retrograde menstruation. Tomioka compares the number of ovulatory cycles in women 200 years ago with today.
- •About 50% heritability, with roughly sevenfold higher risk with a first-degree relative
- •About 90% of women have retrograde menstruation, so it is probably necessary but not sufficient
- •Immune dysregulation may keep macrophages from clearing the tissue
- •Modern women have roughly four times as many ovulatory cycles as women 200 years ago
- •Hormonal treatment is a way to mimic the historical reproductive pattern
- 9:02 – 13:25
Estrogen Dependence, Progesterone Resistance and Tumor-Like Lesions
Tomioka describes how lesions make their own estrogen through aromatase and resist progesterone. Peter Attia ties this to menstrual cycle physiology. They also discuss the cancer-like mutations in lesions and why they stay benign.
- •Lesions overexpress aromatase and produce their own estrogen
- •Progesterone resistance means much more progesterone is needed for an effect, which Attia likens to insulin resistance
- •Somatic mutations such as KRAS and PIK3 appear in up to 37% of deep lesions and adenomyosis
- •Lesions do not metastasize, likely because of adhesions and fibrosis
- •Tomioka uses the image of an F1 engine in a golf cart
- 13:25 – 18:58
Adenomyosis: How It Differs from Endometriosis
Tomioka calls adenomyosis the missed disease and explains it is endometrial-like tissue within the myometrium. He covers prevalence, overlap with endometriosis, the tissue injury and repair mechanism, and who gets it.
- •Adenomyosis affects up to 20–30% of women, and up to 70% of endometriosis patients may have some degree of it
- •It is molecularly distinct from endometriosis but shares oncogenic mutations, progesterone resistance and aromatase overexpression
- •Proposed mechanism is tissue injury and repair at the junctional zone
- •Miscarriage, C-section, curettage and hysteroscopy can break the boundary
- •It is now seen in younger women, even without pregnancies
- 18:58 – 25:28
Recognizing the Symptoms: The Six Ds and Fibroids
Tomioka presents the six Ds of endometriosis and contrasts them with adenomyosis, which mainly presents with heavy bleeding. They add a detour on fibroids and why submucosal location matters.
- •Six Ds: dysmenorrhea, deep dyspareunia, dyschezia, dysuria, difficulty conceiving, and dysfunctional chronic pelvic pain
- •About 10% of endometriosis patients are asymptomatic or normalize their pain
- •Adenomyosis mainly presents with heavy uterine bleeding and anemia; perhaps a third are asymptomatic
- •Fibroids are common benign nodules; FIGO types 0–2 (submucosal) matter most for bleeding and fertility
- 25:28 – 28:27
Why Endometriosis Hurts: Three Pain Types and Central Sensitization
Tomioka explains three kinds of pain in endometriosis and how surgery and hormones address each. He uses a burglar and alarm analogy for central sensitization, which is why early treatment matters, and mentions the new ACOG guidance allowing empiric treatment.
- •Nociceptive pain comes directly from lesions and responds to surgery and hormones
- •Nerve-involving pain may need gabapentin or SNRIs, or nerve-sparing surgery
- •Central sensitization persists after lesions are removed and needs pelvic floor physiotherapy and pain specialists
- •ACOG's March 2026 guidance allows clinical diagnosis and empiric treatment
- 28:27 – 33:11
Endometriosis in Teenagers and Delayed Diagnosis
The conversation turns to rising prevalence in teenagers and possible environmental contributors. Tomioka then explains why diagnosis takes five to twelve years, citing cultural normalization of pain, no simple biomarker and reliance on laparoscopy.
- •Up to 50–75% of teenagers with pelvic pain have endometriosis
- •Possible contributors include microplastics, pollution, diet and poor sleep, though data are not definitive
- •Diagnostic delay is about six years in the US and seven in Brazil
- •Economic cost estimated at $80–120 billion per year, two-thirds from lost productivity
- •Diagnostic laparoscopy should no longer be the default
- 33:11 – 45:52
Modern Imaging: Specialized Ultrasound and MRI
Tomioka explains that a routine ultrasound can miss endometriosis. The better tools are an expert ultrasound protocol with bowel prep and MRI, each with strengths and gaps in availability and anatomy.
- •A normal ultrasound has very low sensitivity; a negative report does not rule out disease
- •Three ultrasound tiers: regular, augmented with sliding sign, and detailed protocol with bowel prep
- •The detailed protocol is limited in the US because it takes about an hour and needs expertise
- •MRI is non-contrast T1/T2 and better for diaphragm, lateral pelvis, ureter and nerves but weaker for bowel disease
- •Ultrasound is essential before planning surgery
- 45:52 – 55:36
Treatment for Pain Without Immediate Fertility Goals
Using hypothetical patients posed by Attia, Tomioka walks through medical therapy as first line for a 20-year-old and a woman in her late 30s with two children. He explains the choice among Mirena, progestin-only pills and combined pills, and why surgery alone often leads to recurrence.
- •Key questions include desire for pregnancy, ovarian reserve and whether an endometrioma is present
- •Mirena suits patients without endometrioma or myofascial pain; otherwise progestin-only or low-dose combined pills
- •Recurrence after excision is about 10% per year without medication; a Mirena after surgery was linked to 88% lower recurrence
- •Endometriosis should be managed as a chronic disease over a lifetime
- 55:36 – 1:11:52
Endometriosis and Fertility: Mechanisms, Aneuploidy and IVF
For a 36-year-old who wants a baby, Tomioka discusses the fertility workup and mechanical tubal damage, and why donor-egg data suggest endometriosis alone may not impair implantation. They then cover how aneuploidy rises steeply with age and why IVF is often the way to go.
- •Infertility is a couple's disease; male factor and other workups are needed
- •Endometriosis infertility is thought to be mainly mechanical, and surgery can sometimes restore anatomy
- •Women with endometriosis may get fewer oocytes and embryos but similar quality at matched ages
- •Hysterectomy with salpingectomy is the only surgical cure for adenomyosis
- •Aneuploidy is about 35% at 30–35, about 40% at 35, about 60% at 38, and 80–85% by 42
- 1:11:52 – 1:20:53
Surgery Indications, Staging Limits and Adenomyosis After Failed Transfers
Tomioka covers when surgery is indicated even without symptoms, and the limits of the ASRM staging system. He then addresses a 32-year-old with adenomyosis and failed IVF transfers, explaining GnRH suppression before frozen embryo transfer.
- •Red flags for surgery include large endometriomas, small bowel lesions, ureteral involvement and appendix lesions
- •ASRM stage does not match pain or fertility; the endometriosis fertility index predicts post-surgery pregnancy
- •GnRH agonists or antagonists before transfer can raise implantation and lower miscarriage rates
- •Adenomyosis involving the junctional zone brings roughly three times the miscarriage risk
- •Early diagnosis might avoid about 40% of disease burden, though data are limited
- 1:20:53 – 1:28:31
Research Funding Gap and Surgical Pitfalls
Tomioka attributes the scarce research to underfunding relative to disease burden and growing awareness. Attia then poses a case of severe symptoms in a woman who wants to conceive later, and Tomioka lists common surgical mistakes.
- •NIH invests about 15 times more on diabetes than endometriosis despite higher per-patient cost for endometriosis
- •For a woman who will try to conceive, medical therapy has no cumulative effect after stopping, so surgery may be preferred
- •Biggest mistake is operating when central sensitization is the main pain driver
- •Stripping endometriomas can cut AMH by 40–50%, so eggs may be harvested first
- •Leaving a damaged tube (hydrosalpinx) can halve IVF chances, so salpingectomy is needed
- 1:28:31 – 1:34:21
Fertility Misconceptions: Age, the J Curve and Human Reproductive Inefficiency
Tomioka stresses that age is the most underappreciated factor in fertility. He explains the J-shaped aneuploidy curve with a sweet spot around 25, and why human reproduction is inefficient.
- •Even doctors underestimate age; he shows patients a table of aneuploidy rates by year
- •The aneuploidy curve is J-shaped, with higher risk of monosomy in very young women
- •About 20–25% of embryos are aneuploid even at 25
- •Humans lose about 1,000 eggs per month to produce one ovulation, and IVF makes more embryos but doesn't improve quality
- •Euploid embryos give similar pregnancy rates across ages
- 1:34:21 – 1:45:07
Elective Egg Freezing: Timing, Cost and the Fertility Funnel
Attia asks whether a 25-year-old should freeze eggs. Tomioka discusses the low return rate, costs, expected yield and the funnel from follicles to a baby, with cost-effectiveness favoring the early-to-mid 30s.
- •Only about 10% of women who freeze eggs come back to use them
- •In Brazil one cycle costs about $5,000 US, with storage about $150 per year
- •Roughly 15 eggs at a young age give over 80% chance of at least one baby
- •The funnel runs from follicles to mature oocytes (~75%) to blastocysts (30–60%) to euploid embryos
- •Access, not technology, limits wider use
- 1:45:07 – 1:56:37
Emerging Fertility Technologies and IVF Unknowns
They discuss mitochondrial replacement therapy, ovarian tissue freezing and stem-cell-derived eggs, none of which fix the age-related chromosomal problem today. Tomioka also raises epigenetic concerns about IVF.
- •Mitochondrial replacement addresses cytoplasm, not nuclear chromosomal errors, and Tomioka calls clinics' 'egg rejuvenation' claims misleading
- •Ovarian cortex freezing aims mainly to postpone menopause and has little published data
- •Stem-cell-derived eggs are done in mice, and Tomioka estimates about 10 years for humans
- •Epigenetics is his main worry about IVF, though selection bias confounds the data
- 1:56:37 – 2:00:25
Looking Ahead: New Guidance, Biologics and Closing Message on Earlier Diagnosis
Tomioka says he is most excited about the new ACOG guidance and a prolactin receptor antibody in phase III that could be the first non-hormonal biologic. Attia closes by urging patients to push for a diagnosis in months rather than years.
- •ACOG guidance may let clinicians modify disease progression early and avoid infertility
- •HMI115, a monoclonal antibody against the prolactin receptor, is in phase III
- •The goal is cutting diagnostic delay from six or seven years to six months
- •Tomioka says patients should seek a second opinion if told their pain is normal
- •He remembers patients who cry from relief at finally having a diagnosis
