397 - Endometriosis and adenomyosis: diagnosis, fertility, reproductive aging, & emerging treatments

KEYPOINTS

• 01

  Endometriosis affects about 10% of reproductive-age women (around 200 million) and is found in 30–50% of infertile women.

  It's endometrium-like tissue (glands and stroma) growing outside the uterus: on the tubes, ovaries, bowel, bladder, appendix, even the diaphragm. Brazilian reproductive surgeon Dr. Renato Tomioka puts the chance of infertility with endometriosis at about 40%. Heritability is around 50%, and a mother or sister with it raises a woman's risk about sevenfold.

• 02

  Modern reproductive patterns mean about four times more retrograde menstruation than 200 years ago.

  About 90% of women have some menstrual flow back through the tubes into the pelvis, but only those whose immune system (macrophages) can't clear it seem to develop disease. A woman two centuries ago, with first period at 16, first pregnancy at 20, five to seven children and two years of breastfeeding each, had around 100 cycles; today's woman has about 400. Tomioka sees hormonal suppression partly as a way to mimic that ancestral pattern. Microplastics, pollution, diet and poor sleep are suspected but unproven contributors to rising rates.

• 03

  Lesions make their own estrogen, resist progesterone and carry cancer-type mutations, but don't spread like cancer.

  They overexpress aromatase, so suppressing the ovaries isn't always enough, and their progesterone receptors are downregulated, much like insulin resistance. Up to 37% of deep lesions and adenomyosis carry KRAS or PIK3CA mutations. Tomioka's analogy: a 1,000-horsepower F1 engine in a golf cart, because surrounding fibrosis and adhesions stop it from metastasizing.

• 04

  Adenomyosis, endometrial tissue inside the uterine muscle, is a separate disease affecting perhaps 20–30% of women.

  It shares estrogen dominance, progesterone resistance and the same mutations, but single-cell studies show different molecular pathways. Up to 70% of women with endometriosis may also have some adenomyosis. The model is 'tissue injury and repair': the junctional zone between endometrium and muscle is breached, with miscarriage, C-section, curettage and hysteroscopy as risk factors. Once seen mainly in women in their 40s, it now shows up in younger women who have never been pregnant. It mostly causes heavy bleeding and anemia; only hysterectomy cures it.

• 05

  The '6 Ds' of endometriosis.

  Dysmenorrhea (period pain that painkillers don't fix, sometimes needing IV drugs in the ER), deep dyspareunia (pain with intercourse), dyschezia (pain with bowel movements), dysuria (cyclic pain with urination), difficulty conceiving, and dysfunctional chronic pelvic pain lasting over six months. About 10% of women with endometriosis have no symptoms, or their only sign is infertility.

• 06

  Pain has three layers, and the third outlasts the disease.

  Nociceptive pain from the lesion responds to surgery and hormones. Neuropathic pain from nerves invaded by lesions may need gabapentin or SNRIs and nerve-sparing surgery. Nociplastic pain (central sensitization) can persist even after a perfect surgery. Tomioka's analogy: surgery removes the burglar and hormones lock the door, but after years of ringing the rewired alarm goes off in the wind. Diagnostic delay drives that rewiring.

• 07

  Diagnosis takes 5–12 years (about 6 in the US, 7 in Brazil), and a normal routine ultrasound doesn't rule it out.

  The reasons are normalization of women's pain, no blood biomarker, and a tradition of diagnostic laparoscopy. A specialist 'detailed protocol' transvaginal ultrasound with bowel prep (enema an hour before, low-residue diet, vaginal gel) can show bowel-wall layers and uses the 'sliding sign'; it takes about an hour, so few US centers offer it. MRI (non-contrast T1/T2) is also highly sensitive (around 95–98%) and better for the diaphragm and pelvic side walls but weaker for bowel lesions. Tomioka uses both before surgery.

• 08

  Hormonal therapy is first-line for pain, because surgery alone tends to recur.

  For a 20-year-old not trying to conceive, start with a low-dose combined or progestin-only pill, or a hormonal IUD (Mirena or Kyleena) if she has no endometrioma and no myofascial pain, and reassess in 3–6 months. Without medication after surgery, recurrence runs about 10% a year, largely disease too small to see. One study found a Mirena after surgery cut recurrence by about 88% versus placebo. Treat it as a lifelong chronic disease, not a one-off procedure.

• 09

  Endometriosis infertility is mainly mechanical, and age outweighs everything.

  Adhesions damage tube function. Older donor-egg studies found similar implantation and live-birth rates with or without endometriosis, though affected women yield fewer eggs and need more IVF cycles. Aneuploidy, mostly from egg meiosis errors, runs about 20–25% at 25, 30–35% at 30–34, about 40% at 35, 60% at 38, 70% at 40 and 80–85% after that. Very young women also have slightly more monosomies, so the curve is J-shaped with a sweet spot around 25.

• 10

  Adenomyosis lowers IVF success by about 30%, but pre-transfer suppression helps.

  Failures often come at 6–8 weeks, as junctional-zone contractions expel the embryo; involvement of the junctional zone triples miscarriage risk. Two to four months of a GnRH agonist (Lupron or goserelin) before a frozen transfer, then low estrogen and high progesterone, raises implantation and live birth rates. The oral antagonists elagolix and relugolix look similar in one study but cost about $1,000 a month.