Treatments
Primary Goal of Medical Therapy
The main goal of medical treatment for endometriosis is to relieve pain by inhibiting the growth and activity of endometriotic lesions. Doing so, therapy also helps reduce the risk of disease progression and recurrence after surgical treatment.
As a hormone-dependent condition – characterised by heightened sensitivity to estrogen and relative resistance to progesterone – the cornerstone of the treatment is hormonal therapy. These medications aim to rebalance the endocrinological alterations seen in affected patients. Typically taken continuously, these therapies are designed to induce amenorrhea (absence of menstruation) and suppress ovulation, making them incompatible with attempts to conceive during treatment. Their effectiveness is limited to the duration of use, within only rare instances of prolonged benefit after discontinuation.
GnRH Analogs
Pharmacology and Mechanism of Action
GnRH analogs (e.g., triptorelin, leuprolide, buserelin, and goserelin) are molecules composed of a hypothalamic decapeptide capable of modulating the synthesis and secretion of gonadotropins. They act on the pituitary gland to suppress gonadotropin release, thereby inhibiting ovarian stimulation. This results in a near-complete shutdown of estrogen production, creating a temporary, reversible state of pharmacological menopause.
These agents have proven effective by gradually inducing the atrophy of endometriotic lesions.
However, side effects due to the low estrogen levels – such as hot flashes, vaginal dryness, reduced libido – can occur. Notably, the risk of bone mineral loss limits their use to a maximum of 6 consecutive months. To mitigate side effects, “add-back” therapy with low doses of estrogen and progesterone may be prescribed.
Mechanism of Action
Continuous administration of progestins suppresses GnRH and gonadotropin release, thereby reducing ovarian stimulation and inducing anovulation and amenorrhea in a hypoestrogenic environment.
The therapeutic aim is to induce decidualization (transformation of endometrial tissue) and atrophy of endometrium, with partial reabsorption of ectopic endometrial tissue.
Progestins also prevent the implantation and growth of ectopic endometrial tissue by blocking angiogenesis and certain molecular pathways, including metalloproteinase expression, that mediates the tissue response to estrogens. Additionally, they have anti-inflammatory properties, confirmed by both in vitro and in vivo studies.
Progestins are available in various forms: tablets for oral administration, preparations for intramuscular injection, subcutaneous implants, and intrauterine devices.
Dienogest is an oral progestin specifically formulated for endometriosis. A daily dose of 2 mg has shown significant effectiveness in reducing pelvic pain in patients with endometriosis compared to placebo. Its efficacy is comparable to GnRH analogs like leuprolide and triptorelin.
Dienogest is well tolerated, with few side effects. Notably, treatment with dienogest does not appear to be associated with a significant reduction in bone density. Headache, nausea, and vaginal spotting are common side effects, especially in the first months of administration.
Other molecules commonly used in the treatment of endometriosis, with oral and continuous administration, are norethisterone acetate and medroxyprogesterone acetate.
Levonorgestrel is a potent progestin with androgenic and anti-estrogenic activity at the endometrial level. Intrauterine devices with controlled release of 20 mg/day of levonorgestrel (Lng-IUD) have been used for the medical treatment of endometriosis. In particular, this device may be indicated for the treatment of dyspareunia and menometrorrhagia in patients with uterine adenomyosis who do not wish to become pregnant.
Danazol is an oral androgenic agent that interferes with progesterone receptors present at the endometrial level or on endometriotic cells, raising androgen levels and modifying estrogen receptor activity. It also exerts anti-inflammatory and antiangiogenic effects. Common side effects include weight gain, fluid retention, breast atrophy, hot flashes, and signs of hyperandrogenism such as acne and hirsutism. However, vaginal administration of danazol seems to reduce these effects, while maintaining a good therapeutic efficacy.
Combined estro-progestin therapies suppress the release of GnRH by the hypothalamus and gonadotropins by the pituitary gland, thereby reducing the stimulation of spontaneous ovarian activity and inducing anovulation and amenorrhea. This hormonal environment inhibits the growth of endometriotic lesions, reduces menstrual bleeding and decreases uterine contractility – leading to symptom relief and limiting further lesion development.
Continuous administration appears to be more effective for symptom control. Low-estrogen formulations are preferred to minimize estrogen’s stimulating effects on endometriotic tissue.
As with the other hormonal therapies, their benefits are limited to the treatment period. In the case of prolonged therapies, a potential rebound-type negative effect has been observed after discontinuation. This phenomenon may be partly explained by the widespread use of estro-progestins to manage dysmenorrhea, often without a confirmed diagnosis of ongoing endometriotic disease.
Aromatase is a cytochrome P450 enzyme that catalyzes the biosynthesis of estrogens through the conversion of androgens into estrogens. Notably, both endometriosis and extra-ovarian endometriotic implants exhibit elevated levels of aromatase expression. Anastrozole and letrozole, two non-steroidal aromatase inhibitors, act by inhibiting this enzyme and thereby reducing estrogen production.
Two observational studies have examined the use of aromatase inhibitors in combination with either a progestin or an oral contraceptive in premenopausal women with endometriosis that was unresponsive to previous medical or surgical treatment. Both studies reported beneficial effects in treating disease symptoms without serious side effects. Additionally, a randomized clinical trial assessed the efficacy of combining an aromatase inhibitor with a GnRH analog versus using the GnRH analog alone in 80 patients with severe post-surgical endometriosis. Over a 6-month period, the combination therapy proved more effective in alleviating pain, with no observed negative impact on the bone mineral density or overall quality of life.
More recently, a prospective study compared the effectiveness and tolerability of letrozole (2.5 mg/day) combined with norethisterone acetate versus norethisterone acetate alone in women with recto-vaginal endometriosis. The results showed that the combined therapy was significantly more effective in reducing dysmenorrhea and dyspareunia than norethisterone acetate alone.
Medical therapy
The goal of medical therapy is to control pain symptoms and the progression of lesions, as well as to reduce the risk of disease recurrence after surgery. These goals are more likely to be achieved through the pharmacological induction of amenorrhea (absence of menstruation) by administering therapy on a continuous basis. It is important to emphasize that amenorrhea is not menopause, as the hormone taken (progestin or estrogen-progestin) satisfies the body’s metabolic needs.
It should be noted, however, that currently there are no “curative” treatments in the sense that the effectiveness of the medication is maintained only during the treatment period and, in some cases, for a few months after discontinuation. In most cases, once therapy is stopped, the disease may resume its course (both in terms of symptoms and possible lesion growth).
Therefore, these therapies are generally to be administered over the long term (months/years), and should be discontinued—unless contraindicated—only when seeking pregnancy or upon reaching menopause.
The most recommended treatment in terms of the balance between effectiveness and side effects is continuous progestin therapy (dienogest or norethisterone acetate). Often—but not always—this therapy may also lead to a reduction in the size of the lesions, particularly those affecting the ovaries and uterus (adenomyosis), whereas the effect is significantly less on deep and infiltrating lesions.
Common side effects include nausea/headache, spotting (vaginal bleeding), breast tenderness especially during the first weeks of use, mild bloating, and increased appetite.
An alternative solution for long-term therapy is the use of estrogen-progestin combinations, which are more effective when administered continuously rather than cyclically. These have similar side effects to progestins, though generally less pronounced, albeit with sometimes reduced effectiveness. The IUD is generally more suitable for patients with adenomyosis who are not seeking pregnancy.
Although the risks are minimal, the potential impact on breast tissue and increased coagulation activity (higher thromboembolic risk) must be considered for the above-mentioned medications. Therefore, the appropriateness of hormonal therapy is assessed by the physician based on anamnesis, blood work, and breast evaluations to rule out specific contraindications. GnRH analogs are extremely effective in disease control but are associated with significant side effects (they induce a true menopause—complete absence of circulating hormones), making them unsuitable for long-term use.
Surgical Treatment
Surgery for endometriosis may become necessary in three cases:
- Intestinal stenosis with a risk of subocclusive or occlusive episodes
- Ureteral stenosis with risk of impaired kidney function
- Adnexal mass with features suggestive of malignancy
In all other cases, the decision to proceed with surgery must be based on a proper assessment of the risks and benefits.
Once surgery is indicated, the procedure should perform a radical excision, meaning the complete removal of all visible endometriotic lesions. This approach aims to minimize the need for repeat surgeries and the associated complications.
LAPAROSCOPY (a minimally invasive surgical technique) is widely regarded as the “gold standard” (treatment of choice) for endometriosis surgery. It offers significant advantages over traditional open abdominal technique (laparotomy), including:
- Magnified vision with greater surgical precision
- Reduced blood loss
- Lower risk of postoperative adhesions
- Less postoperative pain
- Faster recovery and shorter hospital stay
- Better aesthetic results
In some cases, depending on the type of surgery planned, bowel preparation may be required, starting approximately 24 hours before the procedure.
The surgery is performed under general anesthesia (with orotracheal intubation) using fine instruments and a small camera (laparoscope), inserted into the abdomen through micro-incisions (5 to 12 mm). The procedure always involves the insufflation of the abdominal cavity with carbon dioxide (CO₂), which is quickly reabsorbed after the surgery.
The duration of the procedure varies depending on the complexity of the anatomical region. As is standard practice for all surgical procedures, a venous access is placed for the administration of necessary medications. After sedation, a urinary catheter is placed, usually removed immediately after surgery, before awakening, unless clinically indicated otherwise.
At the end of the procedure, an abdominal drain and/or a nasogastric tube may be used and typically removed within a few days.
For certain urinary tract procedures, a ureteral stent may be placed internally to keep the ureter open. Its removal depends on the specific case and clinical needs.
Blood or plasma transfusions are very rarely required.
Although complications are extremely rare, our facility is equipped with a Postoperative Intensive Care Unit (T.I.P.O.), staffed 24/7 by experienced anesthesiologists and nurses.
The return to normal eating in the postoperative period depends on the natural recovery of intestinal function. In most cases, this occurs early – except in surgeries directly involving the intestinal loops, where a slightly longer delay may be required. Whenever possible, early mobilization is encouraged to promote a faster postoperative recovery.
The average hospital stay is 48 to 72 hours. In more complex procedures, involving the intestines, urinary tract or bladder, hospitalization may last up to 7 days or more.
After surgery, moderate discomfort around the incision sites is common and usually manageable with standard pain medication. Patients may experience paresthesia or hypoesthesia, which are mild alterations in skin sensitivity – such as numbness, tingling, or warmth – especially in the abdominal area or lower limbs (inner thighs). These effects are generally due to the patient’s positioning during surgery and tend to resolve spontaneously within a few days (in rare cases, they may persist for a few weeks).
Our operating rooms are equipped with state-of-the-art technology, including dedicated systems for advanced endoscopic surgery and 3D visualization tools, allowing for even greater precision and safety.
Endometriosis is often a “multivisceral” disease, meaning it affects multiple organs and compartments. As a result, surgical treatment must address multiple areas, making the benefits and risks of the procedure a complex equation.
This equation depends on several factors, including: the specific anatomical compartments affeccted, any previous surgeries, the extent of anatomical damage caused by the disease, the patient’s individual healing capacity and recovery response.
Excision of deep endometriosis typically requires access to the retroperitoneum (the space between the pelvic bones and the peritoneum, which contains crucial structures such as blood vessels, nerves, and lymph nodes). This makes the identification and isolation of the ureters and surrounding neurovascular structures a fundamental part of the surgery.
Given the disease’s tendency to affect multiple systems, surgery may often require not only gynecological procedures (affecting the uterus and adnexa), but also urological, neurological and colorectal surgical procedures.
According to current national guidelines (SIGO-AOGOI-AGUI 2018), these surgeries can be performed either by a pelvic surgeon (a gynecological specialist with proven expertise in these procedures) or by a multidisciplinary team, including a gynecologist, a general surgeon and an urologist.
At our facility, all surgeries are performed by a dedicated team of expert gynecologic surgeons, specialized in advanced treatment of abdominopelvic endometriosis.
Their extensive experience is also demonstrated by the volume of procedures performed, with approximately 800 surgeries per year.
Surgical treatment for ovarian endometriosis is indicated in cases when a cyst shows suspicious features suggesting malignancy (a rare event, <1%, especially in younger patients). Our facility offers daily pathology services for intraoperative histological examination. However, the final evaluation always relies on the definitive histological analysis.
A surgical approach may also be required, regardless of the absolute size of the cystic formation, in cases where the mass presents typical features and does not respond to medical therapy – either due to persistent pain or an increase in size. Surgery is also indicated for symptomatic patients who cannot take pharmacological treatment. Another potential indication is for infertile patients undergoing assisted reproductive procedures (PMA) if the cyst presents an obstacle to the treatment.
The preferred surgical technique is cyst evacuation with capsule removal (stripping). Any ovarian surgery has the potential to reduce the ovarian follicular reserve, a factor that must be carefully considered, especially in young reproductive-age patients. In such cases, combined strategies involving medical therapy and/or oocyte cryopreservation before or after surgery may be evaluated. Numerous scientific studies highlight that the surgeon’s experience and the specific techniques used are crucial in preserving as much healthy ovarian tissue as possible. However, even with expert techniques, some reduction in residual ovarian tissue must be considered.
At our center, the most advanced technologies (Diode Laser, Argon, PlasmaJet) are routinely used to minimize ovarian damage when cystic lesions need to be removed. The risk of compromising the follicular reserve is higher in patients with a history of ovarian surgery and in cases where bilateral intervention is required. For this reason, in the presence of small-volume lesions, a simple drainage procedure is sometimes preferred, avoiding capsule removal. Implementing these measures helps reduce the risk of early menopause, which, although generally rare (1-2%), should still be considered. The likelihood of this outcome depends on the patient’s age and baseline follicular reserve.
Retrocervical region – uterosacral ligaments insertion, vagina/rectovaginal septum, parametrium, ureters
A retro-cervical or vaginal nodule is carefully separated from the posterior wall of the uterus and, if adhered, from the anterior wall of the intestine. If the posterior vaginal wall is deeply infiltreted by endometriosis, partial resection may be required, followed by suturing. In such cases, patients must abstain from vaginal intercourse for at least two months to ensure proper healing and prevent suture dehiscence (reopening).
Treatment of lesions in the retro-cervical and parametrial area (lateral or posterolateral to the cervix), whether unilateral or bilateral, always requires visualization of the ipsilateral ureter to ensure surgical safety. Due to their close anatomical proximity to these nodules, ureterolysis (freeing the ureter from surrounding tissue) may be necessary. If the paracervical lesion directly involves the ureter, it may lead to ureteral suffering with possible mechanical narrowing (stenosis) and subsequent urinary obstruction, potentially leading to kidney dilation due to inadequate drainage.
In some cases, ureterolysis is sufficient. In more advanced cases or when irreversible ureteral damage is present, resection of the affected ureter segment, followed by reconstruction (ureteral anastomosis or reimplantation into the bladder) may be necessary. These procedures often require bladder mobilization, temporary ureteral stent and, in some cases, a bladder catheter for several weeks. If preoperative tests reveal significant, irreversible kidney damage, nephrectomy (removal of the kidney) and ureterectomy (removal of the ureter) may be indicated.
The parametrium is a critical “nerve center” containing fibers responsible for bladder, vaginal and rectal function. Surgery in this area requires specialized expertise to minimize the risk of postoperative neurological complications.
Surgical intervention in these areas is highly delicate and complex, aiming to preserve as much of these structures as possible to minimize neurological deficits (“nerve-sparing surgery”). However, endometriotic lesions may already involve these nerve fibers. In some cases, radical excision of disease may necessitate the removal of affected nerve branches. Alternatively, a more conservative approach may be chosen intraoperatively, leaving small residual lesions to reduce the risk of neurological damage, based on a case-by-case risk-benefit assessment.
It is important to note that endometriosis often causes ischemic nerve damage even before surgery, as the disease is “neurotropic” (it has a tendency to invade nerve fibers).
Some patients may also experience symptoms before surgery, such as frequent urination (pollakiuria), incomplete bladder emptying, bowel dysfunction, and, less commonly, sexual dysfunction (e.g., decreased arousal, inability to reach orgasm, chronic vaginal dryness). Some patients also report preoperative postural or walking difficulties due to sensory or motor nerve involvement.
When the disease compresses or infiltrates somatic nerves (such as the sciatic, obturator, or pudendal nerves, which control the perineum), laparoscopic neurolysis or decompression surgery may be performed.
When executed by specialists with expertise in neuroanatomy and neurosurgery, these procedures can provide excellent pain relief and functional recovery. However, because nerve regeneration is slow, full recovery may take several months, and an initial worsening of symptoms in the immediate postoperative period is not uncommon. In some cases, postoperative physiotherapy and targeted rehabilitation can be beneficial.
Intestinal Endometriosis
Intestinal endometriosis can be treated with different surgical techniques, depending on the extent and depth of the lesion:
- Shaving: a superficial excision that removes the lesion from the outer intestinal wall without incising it
- Discoid Resection: removal of a small, full-thickness section of the bowel wall, followed by suturing
- Segmental Resection: removal of an entire segment of the intestine containing the nodule, followed by reattachment (anastomosis) of the remaining sections
The choice of surgical technique depends on:
- Nodule size (length, infiltration depth, transverse diameter)
- Location (intestinal segment involved and distance from the anal margin)
- Percentage of intestinal circumference affected
- Degree of stenosis
- Presence of multiple lesions
The surgical plan is generally based on preoperative evaluations, including consultation and specialized ultrasound (occasionally MRI or other additional tests).
Intraoperative findings may lead to a change in the surgical approach. Shaving is suitable for superficial lesions; discoid resection is used for small, deeply infiltrating nodules and is often performed using a transanal stapler; segmental resection is reserved for larger or multiple nodules and requires a small laparotomy (3–5 cm).
Postoperative feeding usually resumes quickly, although temporary parenteral nutrition may be required in some cases. Protective stomas (ileostomy or colostomy) are rare (<5%) and typically used when intestinal and vaginal resections are combined or for very low resections. These are usually reversed within two months in a second surgery.
Surgical treatment involves excision via a mini-laparotomy. In cases where a large portion of the abdominal wall must be removed, mesh reconstruction may be necessary. If this surgery is not combined with pelvic endometriosis treatment, it can often be performed under regional anesthesia.
The treatment of adenomyosis is currently one of the most debated topics in international scientific literature. As with other forms of endometriosis, treatment is reserved for symptomatic patients or those with infertility issues. In patients who are not seeking pregnancy, common medical therapies for pelvic endometriosis can be employed with reasonable success. These include oral progestins, LNG-IUS (levonorgestrel-releasing intrauterine system), combined oral contraceptives, and, as a last resort, GnRH analogs.
In patients who have completed their reproductive plans or are in advanced perimenopausal age, surgical approach – such as hysterectomy with salpingectomy, with or without oophorectomy – may be considered. These options are not appropriate for patients wishing to conceive.
The main challenge is that adenomyosis – particularly in diffuse forms – cannot be entirely removed surgically, as it affects large portions of the uterine wall and lacks a clear boundary between disease and healthy myometrial tissue. Even in focal forms, the absence of a distinct capsule complicates surgical removal, increasing both complexity and risk.
Certain conservative surgical techniques may be used in selected cases, but, while they can offer short-term symptom relief, they often carry significant obstetric risks, including the possibility of uterine rupture during pregnancy, even long after the surgery.
The procedures described above are conservative surgeries, primarily aimed at restoring normal pelvic anatomy, relieving pain and improving quality of life and fertility in reproductive-aged patients.
In older symptomatic patients or those who have completed their reproductive plans and are unresponsive to medical therapy or have contraindications to it, demolitive surgery may be considered. This may include the removal of the uterus (total hysterectomy), fallopian tubes, and, in some cases, the ovaries.
This decision must be carefully balanced with the consequences of iatrogenic menopause and the need for hormone replacement therapy (HRT).
When a total hysterectomy is performed, it may also be considered, in agreement with the patient, to leave in place any infiltrating endometriotic lesions that are not causing organ damage, especially if their removal would entail excessive surgical risk.
If treatment of parametrial lesions is also necessary during hysterectomy, the techniques and associated risks are the same as described for that anatomical area.
At the end of the procedure, the vaginal wall is sutured. Abstinence from sexual intercourse for at least three months is recommended to ensure complete healing and prevent dehiscence (reopening) of the sutures.