397 - Endometriosis and adenomyosis: diagnosis, fertility, reproductive aging, & emerging treatments
In a Nutshell
Endometriosis and adenomyosis are chronic, estrogen-driven diseases with ~50% heritability that cause pain, heavy bleeding, and infertility through progesterone-resistant lesions, adhesions, and junctional-zone disruption; modern women face fourfold higher lifetime ovulatory cycles than historical norms, driving rising prevalence. Non-invasive diagnosis via expert ultrasound or MRI now replaces routine laparoscopy, enabling earlier treatment that prevents central sensitization, while surgery is reserved for large endometriomas, obstruction risk, or failed medical therapy. Fertility outcomes hinge primarily on age-related aneuploidy and ovarian reserve rather than the diseases themselves; GnRH suppression improves adenomyosis implantation rates, and egg freezing at 32–35 maximizes euploid yield before sharp fertility decline.
These notes were generated by AI and may contain inaccuracies.
The discussion begins by focusing on diseases of the uterus, primarily endometriosis, followed by infertility and associated treatments.
The uterus consists of three main layers: the outer serosa, the middle muscular layer called the myometrium, and the inner endometrium where the embryo implants and the placenta develops. Endometriosis is defined as a chronic disease in which endometrial-like tissue appears outside the uterus, commonly affecting the fallopian tubes, ovaries, bowel, bladder, appendix, and diaphragm.
Endometriosis affects approximately 10% of reproductive-age women globally, equating to roughly 200 million women. Among infertile women, the prevalence rises to 30-50%. Women with endometriosis face approximately a 40% chance of infertility, indicating a causal relationship.
The endometrial layer is dynamic and changes throughout the menstrual cycle. The myometrium contracts during childbirth. The outer serosa functions as visceral peritoneum; endometriosis can occur here and may progress to external adenomyosis.
Endometriosis shows approximately 50% heritability. Women with a first-degree relative (mother or sister) have about seven times higher risk. Twin studies indicate shared genes with incomplete penetrance. Environmental triggers may include pollution. A key factor is repetitive ovulatory menstruation, where retrograde menstruation allows menstrual flow to travel through the fallopian tubes into the pelvis.
Approximately 90% of women experience retrograde menstruation. The fimbriae of the fallopian tubes pick up oocytes from the ovarian surface or cul-de-sac. This process is considered necessary but not always sufficient for endometriosis development. Immune dysregulation, particularly involving macrophages, may impair clearance of endometrial tissue in affected women.
Two hundred years ago, women experienced roughly 100 ovulatory cycles lifetime due to later menarche (age 16), earlier first pregnancy (age 20), extended breastfeeding (2 years per child), and having 5-7 children. Modern women experience approximately 400 cycles, representing a four-fold increase in retrograde menstruation exposure. This shift may explain rising endometriosis prevalence.
Endometriotic lesions overexpress aromatase, producing their own estrogen and rendering ovarian suppression alone insufficient. Progesterone receptors are downregulated, creating resistance that diminishes progesterone's counterbalancing effect on estrogen. This mechanism parallels unopposed estrogen in hormone replacement therapy, which thickens the endometrial lining.
During the late follicular phase, the endometrium reaches 8-10 mm thickness. Progesterone triggers decidualization and the secretory phase, changing endometrial appearance on ultrasound. Without pregnancy, the corpus luteum regresses after 12-14 days, leading to shedding due to declining estrogen and progesterone.
Endometriotic lesions exhibit stroma and glands resembling endometrial lining but demonstrate progesterone resistance, requiring higher progesterone levels for effect. Lesions also harbor somatic mutations in oncogenic genes including KRAS and PIK3, resembling cancer behavior especially in deep infiltrating endometriosis and adenomyosis (up to 37% of lesions). These are benign tumors lacking metastatic potential due to adhesions and fibrosis.
Adenomyosis involves endometrial-like tissue within the myometrium and affects 20-30% of women, exceeding endometriosis prevalence. Previously termed internal endometriosis, it shares mechanisms including somatic mutations, progesterone resistance, and aromatase overexpression but represents a distinct disease based on single-cell transcriptomic studies. Hysterectomy cures adenomyosis as it is confined to the uterus, unlike endometriosis.
Up to 70% of endometriosis patients may have some degree of adenomyosis. Adenomyosis involves tissue injury and repair (TIA) where endometrium invades the junctional zone, creating cysts and echogenic buds that enlarge and soften the uterus.
Risk factors include miscarriage, C-section, curettage, and hysteroscopy for leiomyomas or polyps, which mechanically disrupt the endometrial-myometrial junction. External adenomyosis occurs when deep infiltrating endometriosis invades the myometrium from the serosa.
Traditionally considered a disease of women in their 40s due to prior pregnancies and procedures, adenomyosis now appears in younger nulliparous patients. Endometriosis can present in teenagers, with 50-75% of adolescents with pelvic pain having the condition.
Typical symptoms include: dysmenorrhea (severe menstrual pain sometimes requiring ER intravenous medications), deep dyspareunia (pain during intercourse, especially posterior vaginal wall), dyschezia (pain during bowel movements), dysuria (cyclic pain during urination), difficulty conceiving (infertility), and dysfunctional chronic pelvic pain (pain >6 months unrelated to cycle). Approximately 10% of endometriosis patients may be asymptomatic, with infertility as the sole presentation.
Adenomyosis often presents with heavy uterine bleeding leading to anemia. Asymptomatic cases may represent about one-third of patients depending on phenotype and disease intensity. Single leiomyometrial cysts may be asymptomatic, while diffuse adenomyosis or adenomyomas cause significant bleeding and pain.
Fibroids affect 70-80% of women and are mostly asymptomatic benign nodules. Submucosal fibroids (FIGO classification 0-2) are closest to or within the endometrial cavity and most problematic for fertility and bleeding. Intramural and subserosal fibroids (higher classification numbers) have fewer clinical implications.
Nociceptive pain originates directly from lesions and responds to surgery and hormonal treatment. Neuropathic pain involves nerve infiltration causing burning sensations in legs and back; medications like gabapentin and SNRIs may help, along with nerve-sparing surgery. Nociplastic pain results from central sensitization where the nervous system remains activated even after lesion removal, requiring pelvic floor physiotherapy and pain specialists.
Delayed diagnosis contributes to central sensitization. ACOG guidance from March 2025-2026 supports clinical diagnosis and empirical treatment based on symptoms to prevent disease burden accumulation.
Increasing prevalence may relate to microplastics, pollution, diet (standard American diet), and poor sleep affecting immune regulation and macrophage function.
Diagnosis delay for endometriosis ranges from 5 to 12 years depending on the country, with approximately 6 years in the US and 7 years in Brazil. Three primary factors contribute to these delays. The first is cultural normalization of female pain, where patients are told symptoms are normal and instructed to take anti-inflammatories, despite some teenagers missing school and adults missing work. The estimated annual economic cost is 80 to 120 billion dollars, with two-thirds attributed to productivity loss rather than medications, hospitalizations, or surgeries.
The second factor is the absence of a simple blood biomarker. Diagnosis requires high-quality imaging such as specialized transvaginal ultrasound or MRI. The third factor is the traditional reliance on diagnostic laparoscopy, a surgical procedure performed under general anesthesia involving abdominal insufflation and camera insertion.
The transition toward non-invasive diagnosis began approximately 25 years ago. In Brazil, specialized ultrasonography developed by Dr. Luciana Chamie and Dr. Manorama at Mass General represents a leading protocol. This involves bowel preparation similar to a simplified colonoscopy regimen, including an enema one hour before the exam and a no-residue diet, along with gel insertion into the vagina. This protocol enables visualization of small lesions in the bowel and bladder and assessment of bowel wall layers.
Sensitivity and specificity of both specialized ultrasound and MRI reach 95-98%. However, expertise remains limited. In the US, Mayo Clinic Arizona has Dr. Scott Young performing this protocol, but MRI is more commonly used. The detailed protocol with bowel prep is time-intensive, typically requiring one hour per exam.
Three phenotypes exist: superficial lesions, deep infiltrative endometriosis, and endometriomas (endometriosis cysts). Superficial lesions are defined as less than 5 mm in depth. The most common locations are the posterior compartment including the uterosacral ligaments, ovaries, and fallopian tubes, due to anatomy and gravity. Approximately 80% of diaphragmatic lesions occur on the right side because the sigmoid colon blocks the left side. Bladder involvement occurs in 10-12% of patients. Rectovaginal septum involvement is rare because the space is narrow and lesions typically extend from the uterosacral ligaments.
A normal transvaginal ultrasound without bowel preparation has very low sensitivity for endometriosis. Three layers of ultrasound assessment exist: standard imaging, augmented ultrasound using the sliding sign by pressing the probe against the posterior vaginal wall to assess mobility, and the detailed protocol with bowel preparation performed by an expert.
The sliding sign cannot be assessed by MRI because MRI is static. The ultrasound probe provides 180-degree visualization. Bowel preparation is required specifically to evaluate rectal and bowel endometriosis because stool interferes with imaging; liquid or air contrast is needed. Air is not suitable for ultrasound. The protocol name is the detailed protocol for endometriosis with bowel prep. The device itself is standard; expertise and protocol are what differ.
MRI is performed as non-contrast T1 and T2 sequences, typically with vaginal gel, lasting approximately 20 minutes. Pitfalls include bowel movement artifacts. MRI excels at detecting extra-pelvic lesions such as diaphragmatic disease and lateral pelvic structures including the ureter and nerve infiltration where ultrasound loses echogenicity. MRI is less effective for bowel endometriosis. Patients without rectal symptoms are more likely to have MRI-sufficient diagnoses. For surgical planning, ultrasound remains essential. Both modalities are often used together.
Treatment selection depends on patient goals. Key questions include whether pregnancy is desired in the future, how many children are wanted, ovarian reserve measured by AMH and antral follicle count, disease phenotype particularly the presence of endometriomas, and pain severity.
For a 20-year-old not seeking conception but desiring future fertility preservation, first-line therapy is hormonal suppression. If no endometrioma is present, a levonorgestrel IUD (Mirena) can be used alone, providing five years of treatment through progesterone-mediated endometrial suppression and amenorrhea. If myofascial pelvic pain is present or the patient declines IUD insertion, options include progestin-only pills such as norethindrone or dienogest, or combined oral contraceptives using the lowest effective estrogen dose because estrogen can activate lesions.
If symptoms do not improve after three to six months, medication can be changed or surgery considered. Surgery is generally deferred initially because recurrence rates are high; approximately 10% per year especially with endometriomas when no postoperative medication is used. Endometriosis behaves like a chronic disease requiring long-term management rather than a single intervention.
Surgery involves laparoscopic excision. Even with complete visible lesion removal, microscopic disease remains. Inserting a levonorgestrel IUD after surgery reduces recurrence rates by 88% compared to placebo. Endometriosis should be conceptualized as a lifelong condition similar to type 1 or type 2 diabetes, addressing the patient's entire life trajectory rather than isolated symptoms or single procedures.
For a woman in her late 30s who has completed childbearing with declining AMH and significant pelvic lesions, first-line options include combined oral contraceptives or progestins. In Brazil, dienogest is commonly used; in the US, Natazia (estradiol plus dienogest) can be used with only the active dienogest-containing pills. A levonorgestrel IUD is an alternative. If medical therapy fails, surgery is considered.
When conception is desired, infertility evaluation must address both partners. Male factor assessment via semen analysis is required, along with additional testing such as karyotype and hysterosalpingogram. Endometriosis-related infertility is primarily mechanical rather than biological. Adhesions compromise tubal function by impairing ovum pickup, fertilization within the tube, or embryo transport to the uterus.
Laparoscopic or robotic surgery can restore anatomy when adhesions are moderate. However, when donor egg studies compared women with and without endometriosis using high-quality embryos, implantation, miscarriage, and live birth rates were similar, indicating endometriosis does not significantly impair implantation clinically. Therefore, surgery before frozen embryo transfer is not routinely beneficial for endometriosis alone.
Adenomyosis differs because it cannot be surgically excised without hysterectomy. For women who no longer desire fertility, hysterectomy with salpingectomy is performed; ovarian conservation depends on age and ovarian reserve. Salpingectomy is standard during hysterectomy.
The transcript ends mid-sentence during discussion of donor egg studies showing comparable outcomes between women with and without endometriosis.
Studies comparing IVF recipients with and without endometriosis are often heterogeneous and fail to account for concurrent adenomyosis, which confounds implantation and miscarriage rates. When transferring a good embryo into a uterus of a patient with or without endometriosis, results are essentially the same. However, patients with endometriosis produce fewer oocytes, fewer mature oocytes, and fewer embryos, requiring more IVF cycles. Molecular data indicate oocytes in endometriosis patients are not entirely normal, but clinically, when matched for age, there is no significant difference in embryo quality or aneuploidy rates.
For a woman in her late 30s, both surgical treatment and egg harvesting are offered in parallel, but IVF is prioritized. Aneuploidy rates are approximately 35% at ages 30-34, rising to around 40% at age 35, 60% at age 38, 70% at age 40, and 80-85% at ages 40+. Prime reproductive age is considered 25-30, after which rates decline sharply.
Aneuploidy refers to an abnormal number of chromosomes in the egg. Normal fertilization involves 23 chromosomes from the egg and 23 from the sperm, totaling 46. Errors occur predominantly on the maternal side (93-95%) due to meiotic division problems, resulting in monosomy or trisomy. Monosomy is generally incompatible with life except for monosomy X (Turner syndrome). Trisomy 21 (Down syndrome) is a notable exception where the fetus can survive. At age 30, most embryos are aneuploid, leading to implantation failure and miscarriage risk that is invisible on standard exams.
The recommended approach involves freezing embryos first, then performing surgery if indicated by large endometriomas (over 5-6 cm), significant pain affecting quality of life, small bowel lesions with obstruction risk, or ureteral involvement that could lead to kidney function loss. One documented case involved silent endometriosis causing hydronephrosis and eventual left nephrectomy.
The ASRM classification system (stages 1-4) is primarily a surgical map describing disease extent but does not correlate with pain severity or fertility outcomes. A stage 4 patient may be asymptomatic while a stage 1 patient may experience debilitating pain. The Endometriosis Fertility Index provides a more useful scoring system (0-10) based on tubal, fimbrial, and ovarian quality post-surgery to predict natural pregnancy rates after surgery. Scores of 9-10 correlate with approximately 65% natural pregnancy chance. Low scores or damaged tubes (dilated or requiring salpingectomy) indicate proceeding directly to IVF.
For a 32-year-old with adenomyosis and two failed transfers but remaining frozen embryos, GnRH agonist treatment (Lupron or goserelin) is used for 2-4 months before transfer. This suppresses estradiol to menopausal levels, increasing implantation rates, decreasing miscarriage rates, and improving live birth rates. Oral GnRH antagonists (elagolix, relugolix) are alternatives with fewer side effects but cost around $1,000 per month. Both agonist and antagonist approaches achieve pregnancy and miscarriage rates comparable to patients without adenomyosis.
GnRH agonists initially cause a flare-up effect with increased FSH and LH before downregulating receptors after 2-4 weeks, producing chemical menopause. Antagonists act immediately without flare-up but achieve the same hormonal suppression. Ultrasound monitoring shows minimal morphological change in adenomyosis lesions, though some uterine volume reduction may occur.
Adenomyosis primarily causes pregnancy maintenance problems rather than implantation failure, with losses typically occurring at 6-8 weeks due to junctional zone contractions. Treatment does not substantially shrink lesions morphologically but chemically alters the uterine environment. Endometriosis and adenomyosis increase risks of preterm birth, preeclampsia, small for gestational age infants, and higher cesarean rates. Adenomyosis involving the junctional zone carries three times higher miscarriage risk. Adenomyosis is thought to arise from disruption at the endometrial-myometrial boundary, progesterone resistance, junctional zone contractions, and hypertrophy.
No drugs currently target progesterone resistance directly. Earlier diagnosis and treatment in adolescents or young women could potentially prevent 40% of disease burden, though supporting data is limited. NIH invests approximately 15 times more in diabetes research than endometriosis despite endometriosis costing roughly $16,000 per patient annually compared to $12,000 for diabetes. Increased public awareness through media is gradually improving recognition.
For a 30-year-old with severe symptoms who is not yet trying to conceive, hormonal therapy is not first-line because it controls symptoms only during use and provides no cumulative benefit after discontinuation. Since medications are primarily contraceptive, surgery is preferred to treat pain while preserving natural conception attempts afterward.
Major errors include operating on patients with central sensitization expecting pain resolution, as surgery does not address nociplastic pain—preoperative physiotherapy for 8 weeks followed by postoperative physiotherapy at 2-4 weeks is recommended. Another error is removing all endometriomas during cystectomy, which can reduce AMH by 40-50% by removing adjacent healthy follicles from the ovarian cortex. The presence of endometriomas themselves also decreases ovarian reserve through oxidative stress and follicular burnout. Damaged tubes (hydrosalpinx) should be removed via salpingectomy, as retained hydrosalpinx reduces IVF success by half through both mechanical washing of embryos and embryotoxic cytokine secretion.
Age remains the most critical and underappreciated factor, even among physicians who may encourage natural conception attempts at age 42. Aneuploidy rates are not linear but follow a J-curve pattern, with higher rates at very young ages (around 20) than at 25, then rising exponentially after 30. At age 25, 20-25% of eggs are aneuploid. Human reproduction is inherently inefficient: approximately 1,000 eggs are lost monthly through atresia, only 10-15 follicles develop per cycle with one ovulating, and millions of sperm compete for fertilization. In contrast, mice and rabbits show very low aneuploidy rates and higher reproductive efficiency. Once chromosomally normal embryos are obtained, it is unknown whether eggs from older women differ in other non-visible genetic qualities compared to younger women.
Clinical pregnancy rates using euploid embryos remain similar across ages 30, 35, and 40. Embryologists note that embryos from older patients are often morphologically less ideal and show different morphokinetics, yet the clinical difference in outcomes is not substantial.
For a 25-year-old woman in graduate school or professional training who does not plan to have children for another 5-10 years, egg freezing is not recommended for all patients. Checking AMH to assess ovarian reserve is reasonable. The J-curve effect means the difference in fertility between ages 25, 30, and 35 is significant. If a woman is certain she wants children in the future, discussing egg freezing is appropriate.
Globally, approximately 10% of women who freeze their eggs return to use them. This means 90% of women who undergo egg freezing never use those eggs. Some become pregnant naturally, while others simply do not use the stored eggs. The most cost-effective age range for egg freezing is around 32-35 years old, though biologically earlier freezing is preferable.
In Brazil, one egg harvesting cycle costs approximately $5,000 USD. Annual storage costs are around $150. Costs in the US are also out-of-pocket. Medication accounts for one-third of the cost, with the procedure and laboratory each accounting for one-third.
Approximately 75-80% of embryos from a 25-year-old are euploid. When freezing unfertilized eggs, about 75% of retrieved oocytes are mature and suitable for freezing. With 15 mature eggs frozen at age 25, the estimated chance of having at least one baby exceeds 80%. The process involves attrition at each stage: maturation, fertilization, blastocyst development, and implantation.
The risk of complications from egg retrieval, including ovarian torsion, bleeding, and infection, is approximately 1%.
The median age of women presenting for social egg freezing is 37-38 years old. This is partly because egg freezing is a relatively new treatment option and partly due to selection bias toward more difficult cases.
A typical AMH level for a 40-year-old woman is around 1 ng/mL. Antral follicle count should be checked in both follicular and luteal phases because it varies significantly between cycles. A 40-year-old woman with normal reserve for her age might yield approximately 8 eggs per cycle. At this age, more than half of eggs are expected to be aneuploid, often resulting in only 1-2 euploid embryos available for implantation.
The process of IVF involves multiple stages of attrition. Each follicle contains one oocyte. Approximately 75% of oocytes mature to the M2 stage. From day 1 (pronuclei stage) to day 5-6 blastocyst, 30-60% develop successfully, depending on sperm quality and laboratory conditions. Aneuploidy rates further reduce viable embryos. This compounding inefficiency explains why outcomes can be disappointing even with reasonable starting numbers.
Patients who freeze eggs at age 34 and return at age 40 may find that 8 eggs produce only one blastocyst that fails to implant. Understanding the depth of the attrition funnel is critical for setting realistic expectations.
In countries with fertility rates below the replacement level of 2.1, egg freezing at younger ages could be viewed as a public health investment. Japan is currently facing this demographic challenge. Israel covers unlimited IVF cycles for family building.
Mitochondrial replacement therapy involves transferring the pronuclei from a fertilized embryo into an enucleated donor oocyte with healthy mitochondria. This technology addresses mitochondrial DNA disorders but does not solve the chromosomal problems associated with advanced maternal age. Clinics in North Cyprus and Greece have marketed this as egg rejuvenation, which is considered misleading. The approach swaps the cytoplasmic battery but leaves the nuclear engine unchanged.
Some clinics, including one in the UK, are exploring freezing ovarian cortex tissue years before menopause to postpone menopause and preserve fertility. Patients undergo partial oophorectomy, typically in their 30s, with tissue reimplanted later, potentially in the peritoneum or subcutaneously. Mathematical models suggest menopause could be postponed by 10-15 years or more. This approach is primarily intended to produce endogenous estrogen and progesterone rather than oocytes. Outcomes from ovarian cortex freezing are inferior to standard egg freezing.
The rationale for ovarian tissue transplantation over standard menopausal hormone therapy relates to cultural perceptions of menopause and concerns stemming from the 2002 Women's Health Initiative findings. However, providing estrogen, progesterone, and sometimes testosterone is simpler and avoids premenstrual syndrome-like symptoms that can occur with transplanted tissue.
Stem cell-derived oocytes are estimated to be approximately 10 years away from clinical availability. While possible in mice, human applications require demonstration of chromosomal and genetic normality, followed by safety data after fertilization and transfer. The process is more complex for oocytes than for sperm. If successful, this technology would eliminate the need for egg freezing and potentially allow reproduction at any age.
Even with advancing technology, natural conception remains preferable when possible due to cost and the absence of unknown epigenetic effects. IVF has been available since 1978, yet not all natural tubal processes can be fully replicated in vitro. Epigenetic consequences of IVF remain incompletely understood.
Potential unknown risks of IVF include epigenetic effects that could manifest as malformations, neurological issues, or cardiovascular disease. Epidemiologic data are confounded by older parental age, socioeconomic factors, and underlying infertility. No randomized controlled trials of IVF exist. Some data suggest that when the same couple conceives naturally after requiring IVF, outcomes are similar, pointing to selection bias rather than technology-related harm.
New ACOG guidance on endometriosis and adenomyosis is expected to reduce complications, particularly in adolescents, by enabling earlier diagnosis and treatment. This approach treats the disease and modifies its progression similarly to how statins modify cardiovascular risk. A monoclonal antibody called HMI115 targets the prolactin receptor and is currently in phase 3 trials. It reduces pain and disease progression without using hormones and may represent the first non-hormonal biologic treatment for endometriosis.
Women experiencing symptoms suggestive of endometriosis or adenomyosis should seek diagnosis aggressively rather than accepting that pain is normal. The goal is to reduce the current diagnostic delay of 6 years in the US and 7 years in Brazil down to 6 months. Patients should request MRI and properly protocolled ultrasound and seek second opinions if necessary. Early diagnosis and treatment improve prognosis. The most memorable patient encounters are those in which women cry from relief upon finally receiving a diagnosis and a treatment plan after years of unexplained suffering.
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