Summary of #397 ‒ Endometriosis and adenomyosis: diagnosis, fertility, reproductive aging, and emerging treatments | Renato Tomioka, M.D., Ph.D.

Overview of #397 – Endometriosis and adenomyosis: diagnosis, fertility, reproductive aging, and emerging treatments

In this episode of The Drive, Peter Attia speaks with Dr. Renato Tomioka, M.D., Ph.D., a specialist in reproductive medicine and gynecologic surgery, about endometriosis, adenomyosis, infertility, and age-related fertility decline. The conversation explains what these diseases are, why they’re frequently missed for years, how they’re diagnosed with modern imaging, and how treatment decisions change depending on whether pain control or fertility preservation is the priority. A major theme is that these are chronic, under-recognized conditions that often require earlier diagnosis and a more individualized, long-term strategy.

What endometriosis and adenomyosis are

Endometriosis

• Endometriosis is a chronic disease in which endometrial-like tissue grows outside the uterus.
• Common locations include the:
  • ovaries
  • fallopian tubes
  • bowel
  • bladder
  • appendix
  • diaphragm
• It affects roughly:
  • 10% of reproductive-aged women
  • about 200 million women globally
• It is strongly associated with infertility:
  • 30%–50% of infertile women may have endometriosis

Adenomyosis

• Adenomyosis is the presence of endometrial-like tissue within the uterine muscle wall (myometrium).
• It is often overlooked and may be as common or more common than endometriosis.
• It can behave similarly to endometriosis, with:
  • estrogen dominance
  • progesterone resistance
  • somatic mutations in oncogenic pathways
• Unlike endometriosis, adenomyosis can sometimes be definitively treated with hysterectomy because it is confined to the uterus.

Why these diseases happen and why they are so common

Key risk and biologic factors

• Genetics matter:
  • Heritability is estimated around 50%
  • Having a first-degree relative with endometriosis raises risk roughly 7-fold
• A major biologic driver is retrograde menstruation:
  • menstrual blood flows backward through the fallopian tubes into the pelvis
• Most women likely experience retrograde menstruation, so retrograde flow alone is not enough to cause disease.
• Susceptibility likely also depends on:
  • immune dysfunction
  • estrogen production within lesions
  • progesterone resistance
  • possible environmental contributors such as pollution, diet, microplastics, and sleep disruption

Modern reproductive patterns may increase risk

• Historically, women had far fewer lifetime ovulatory cycles because of:
  • later menarche
  • more pregnancies
  • longer breastfeeding
• Today’s reproductive pattern means many more cycles, and therefore more opportunities for retrograde menstruation-related implantation.
• Dr. Tomioka suggests this may help explain why endometriosis appears more common now.

Symptoms and clinical presentation

Classic endometriosis symptoms: the “6 Ds”

• Dysmenorrhea – severe period pain
• Dyspareunia – pain during intercourse
• Dyschezia – pain with bowel movements, especially during menstruation
• Dysuria – pain with urination, often cyclical
• Difficulty conceiving – infertility
• Dysfunctional chronic pelvic pain – pain lasting >6 months, not limited to the menstrual cycle

Adenomyosis presentation

• More often associated with:
  • heavy menstrual bleeding
  • anemia
  • severe period pain
• Some women are asymptomatic, especially with limited or focal disease.

Important clinical point

• Normalizing severe menstrual pain is a major reason diagnosis is delayed.
• Some patients have symptoms for years before anyone takes the possibility of endometriosis or adenomyosis seriously.

Diagnosis: why it is often missed

Long diagnostic delays

• Average delay from symptoms to diagnosis is about:
  • 5–12 years, depending on country
  • around 6 years in the U.S.
  • around 7 years in Brazil
• The delay is driven by:
  • dismissal of female pain as “normal”
  • lack of a simple blood biomarker
  • overreliance on older surgical diagnosis pathways

Modern imaging is key

• Diagnosis has shifted from routine diagnostic laparoscopy to:
  • specialized transvaginal ultrasound
  • MRI
• A normal ultrasound does not rule out endometriosis.
• Best ultrasound evaluation often requires:
  • a specialized protocol
  • bowel prep
  • an experienced operator
  • dynamic maneuvers like the sliding sign
• MRI is especially useful for:
  • extra-pelvic disease
  • diaphragmatic lesions
  • lateral pelvic disease
  • ureteral and deep infiltrating disease

Practical takeaway

• If symptoms are suggestive, patients should not accept a negative routine ultrasound as the end of the workup.

Treatment strategy: pain control vs fertility preservation

General principle

• Treatment depends heavily on whether the patient:
  • wants symptom relief only
  • wants future fertility
  • is actively trying to conceive

Medical therapy

For patients not trying to conceive right now:

• Combined oral contraceptives
• Progestin-only pills such as norethindrone or dienogest
• Levonorgestrel IUD (Mirena) in selected patients
• Goal: suppress ovulation, reduce bleeding, and reduce estrogen stimulation of lesions

When medical therapy is preferred

• As an initial step for many patients
• Especially if they:
  • do not have large endometriomas
  • do not have major mechanical pelvic distortion
  • are not currently pursuing pregnancy

When surgery is considered

• If symptoms persist despite medical therapy
• If there are:
  • large endometriomas
  • bowel obstruction risk
  • ureteral involvement
  • severe adhesions
  • significant quality-of-life impairment
• Surgery is often laparoscopic excision of lesions and adhesions

Important caution about surgery

• Surgery is not a cure for most endometriosis.
• Recurrence is common, especially without postoperative suppression.
• A key mistake is operating on patients whose main pain is central sensitization, because surgery will not fix that pain pathway.

Endometriosis, pain, and the “three layers” of pain

Dr. Tomioka explains that pain in endometriosis can be:

• nociceptive – pain directly from lesions
• neuropathic / nerve-infiltrating – pain when lesions involve nerves
• nociplastic / centrally sensitized – persistent pain driven by a rewired nervous system

Why this matters

• Even after “successful” surgery, some women continue to have pain.
• These patients may need:
  • pelvic floor physical therapy
  • pain medicine
  • neuropathic pain agents
  • multidisciplinary care

Fertility, IVF, and endometriosis

Endometriosis and infertility

• Endometriosis often causes infertility primarily through mechanical factors:
  • adhesions
  • distorted pelvic anatomy
  • tubal dysfunction
• The issue is often less about embryo implantation failure and more about:
  • failure to pick up the egg
  • failure of fertilization in the tube
  • impaired embryo transport

IVF and endometriosis

• Endometriosis can reduce the number of:
  • oocytes retrieved
  • mature oocytes
  • embryos available
• But once a good-quality euploid embryo is transferred, outcomes may be similar to women without endometriosis.
• This distinction is important:
  • endometriosis may reduce quantity
  • it does not necessarily reduce embryo quality

Endometrioma surgery and fertility

• Removing ovarian endometriomas can reduce AMH and ovarian reserve.
• A major mistake is removing cysts too aggressively before egg retrieval if fertility preservation is a priority.
• In many cases, it is better to:
  1. freeze eggs or embryos first
  2. then consider surgery if needed

Hydrosalpinx

• A damaged, dilated fallopian tube can significantly reduce IVF success.
• Hydrosalpinx may cut IVF success roughly in half, so salpingectomy is often recommended before embryo transfer.

Adenomyosis and fertility

Why adenomyosis matters

• Adenomyosis can impair:
  • implantation
  • pregnancy maintenance
  • live birth rates
• It appears especially problematic when the junctional zone is involved.

Typical treatment before embryo transfer

• GnRH agonists such as leuprolide or goserelin are commonly used for several months before transfer.
• In the U.S., oral GnRH antagonists such as elagolix and relugolix are emerging alternatives.
• These therapies:
  • suppress estrogen
  • create a temporary hypoestrogenic state
  • improve implantation and reduce miscarriage risk

Key fertility takeaway

• Adenomyosis is more likely than endometriosis to affect pregnancy maintenance and miscarriage risk after implantation.

Age-related fertility decline and aneuploidy

Age is the dominant factor

• Dr. Tomioka emphasizes that age is the single most important fertility variable.
• Fertility decline is not linear; it accelerates with age.

Aneuploidy rises sharply with age

Approximate aneuploidy rates discussed:

• around 20–25% of embryos may be euploid even at age 25
• about 30%–35% aneuploidy around age 30–31
• around 40% aneuploidy by age 35
• around 60% by age 38
• around 70% by age 40
• around 80%–85% by early 40s

Clinical implication

• The main age-related problem is usually chromosomal abnormality, not uterine incompetence.
• This is why IVF success drops quickly as maternal age increases.

Egg freezing: when it helps and when it doesn’t

Who may benefit

• Women who:
  • are young now but expect to delay childbearing
  • want to preserve reproductive options
  • may face future fertility threats such as endometriosis

Tradeoffs

• Earlier freezing is biologically better, but:
  • not all women will use the eggs
  • the procedure is expensive
  • many women freeze eggs but never return to use them

Numbers mentioned

• In Brazil, one egg-freezing cycle may cost about $5,000
• Annual storage may cost about $150
• Roughly 10% of women who freeze eggs eventually use them

Big picture

• Egg freezing is useful, but it is not a guarantee.
• The fertility funnel is steep:
  • retrieved eggs → mature eggs → fertilized embryos → blastocysts → euploid embryos → live birth

Emerging technologies and future directions

Mitochondrial replacement therapy

• This is not a solution to age-related infertility.
• It helps in mitochondrial disease, not chromosomal aging of the egg.
• It swaps mitochondria, not the nuclear genetic problem that drives age-related aneuploidy.

Ovarian tissue freezing and transplantation

• Experimental approaches may allow women to freeze ovarian cortex earlier in life and reimplant it later.
• This may eventually help delay menopause or restore hormones/fertility, but data are still limited.

Stem-cell-derived eggs

• A future possibility is creating oocytes from stem cells.
• This is promising in animals, but human safety and long-term outcomes are still unknown.
• Dr. Tomioka thinks it is likely 10 years away, not 5.

New biologics for endometriosis

• He highlighted HMI-115, a monoclonal antibody targeting the prolactin receptor, as a potentially important non-hormonal therapy in development.

Most important takeaways

• Endometriosis and adenomyosis are common, serious, and often dismissed.
• Routine ultrasound can miss disease; specialized imaging matters.
• Early diagnosis improves outcomes and may reduce long-term pain sensitization.
• Treatment must be individualized based on:
  • age
  • pain severity
  • fertility goals
  • ovarian reserve
  • disease phenotype
• Age is the biggest fertility driver, and chromosomal abnormalities rise sharply after 35.
• For many women, the best outcome comes from earlier evaluation, not delayed reassurance.

Practical recommendations for listeners

• If you have:
  • severe period pain
  • pain with sex
  • pain with bowel movements or urination
  • unexplained infertility
  • heavy bleeding
• consider seeking:
  • a second opinion
  • MRI or specialized ultrasound
  • evaluation by a clinician experienced in endometriosis/adenomyosis
• Do not accept “painful periods are normal” if symptoms are disruptive or worsening.