The Current Place of Progestins in the Treatment of Endometriosis

Karl-Werner Schweppe


Expert Rev of Obstet Gynecol. 2012;7(2):141-148. 

In This Article

Clinical Experiences

Oral administration of different progestins at low doses (5–20 mg/day) have been reported, with a wide range of different results reported in mainly retrospective studies. These results, in general, vary little from estrogen–progestin combination therapy; that is, the continuous use of oral contraceptives. These drugs are not, however, labeled for the treatment of endometriosis in most countries. Improvement in subjective complaints varies between 60[11] and 94%.[12] The advantages of progestins in comparison with combined treatment relate to the avoidance of estrogen-induced side effects. The disadvantages mainly relate to spotting and bleeding problems, which have to be treated through increasing dosages, additional estrogen medication or interruption of the medication for 5–7 days. For example, using a dose of dienogest 2 mg daily, the reduction of endometriosis-related pain was significant; however, in 95% of cases spotting was reported, which persisted in 60% of women, even with increased doses of 4 and 6 mg/day.[13] In comparison, breakthrough bleeding and spotting were only reported in 25% of patients using 10 mg/day doses of norethisterone acetate, which was tested in the same study.

Results in Patients With Pain

Two recent published prospective randomized studies tested dienogest 2 mg daily against placebo[14] or versus leuprorelin depot,[15] and showed in the verum group a significant improvement in endometriosis-related symptoms, and a similar effectiveness to GnRH agonist therapy. Bleeding problems were the main side effects and occurred in up to 80% of patients within the first 3 months of treatment, and were reduced during the following months of medication. After finishing the abovementioned placebo study, the women (n = 168) were enrolled in a long-term treatment study (up to 53 weeks) and a 6-month follow-up.[16] The drug showed a good safety and efficacy profile, with a progressive decrease in symptoms and bleeding irregularities during medication use, and the decrease in pain persisted for at least 6 months after cessation of therapy. Dienogest is a special progestin, which does not reduce sex hormone-binding globulin, is bound unspecifically to albumin and does not accumulate using oral doses of 2 mg/day.[17] It has typical progestogenic properties: good tolerability, antiandrogenic action and weak antigonadotropic activity, combined with typical characteristics of 19-norprogestins: strong suppressive action on the endometrium in low doses, a short half-life and high bioavailability.[18]

In a prospective, randomized trial with MPA, Telimaa et al. reported a 50% regression rate of ectopic implants and 13% partial regression with scar formation in the treatment group and 12 and 6%, respectively, in the placebo group.[19] Pain reduction with MPA was as effective as danazol – the standard medication at that time – using medication after diagnosis of endometriosis or after surgical excision as well.[20] Similar results were demonstrated in a prospective randomized study[21] comparing high-dose medrogestone with danazol.

In deep-infiltrating rectovaginal endometriosis, the guidelines[22] recommend complete excision, but it is also possible to treat with progestins symptomatically. This was shown in a prospective randomized controlled trial using norethisterone acetate (NETA) versus a combination of estrogen and cyproterone acetate (CPA).[23] Dyschezia, pelvic pain, deep dyspareunia and dysmenorrhea were reduced significantly with both treatment regimens. The effects of norethisterone acetate in symptomatic pain relief were confirmed in a comparative study using NETA alone versus NETA combined with an aromatase inhibitor.[24] The positive effects of CPA were also observed in a prospective randomized controlled trial using CPA monotherapy for 6 months versus an oral contraceptive for the treatment of endometriosis-related complaints, and the quality of life and psychiatric profile improved significantly in the treated women.[25]

There are only four prospective randomized studies in the literature comparing GnRH analogs with low-dose progestins. In a double-blind study Bergqvist and Theorell found significant reduction of pain symptoms during and 1 year after treatment, but no differences between the medications used.[26] Vercellini et al. used ethinylestradiol 0.02 mg and desogestrel 0.15 mg versus goserelin 3.6 mg monthly,[27] Regidor et al. applied lynestrenol 5 mg daily versus leuprorelin 3.7 mg monthly[28] and Strowitzki et al. tested dienogest 2 mg daily versus leuprorelin depot monthly injections.[15] The Italian group reported a significant reduction of deep dyspareunia and cyclic pain in both groups, with goserelin superior to the oral contraceptive at linear analog scale assessment. Non-menstrual pain was diminished without differences between treatments. Using repeat laparoscopy, the German group found a significantly more pronounced reduction of endometriotic implants in the leuprorelin group (reduction of the r-American Fertility Society score from 21.8 to 11.5 points with leuprorelin and from 27.2 to 25.5 points with lynestrenol; p < 0.000014 Wilcoxon test). The improvement of symptoms like chronic pelvic pain and dyspareunia did not differ significantly. The authors conclude that, primarily, a medication with GnRH agonists is indicated, but that progestins are also very useful for long-term treatment or repeated medication. The most recent study using clinical criteria found a similar effect on endometriosis-related complaints with both medications, but differences in the side effects.[15] In conclusion, different progestins have different effects on the different types of endometriotic foci. Pain relief using adequate dosages of progestins is identical with the medication of danazol or GnRH analogs. Systematic examinations of different progestins in different dosages are lacking and we have no data from prospective randomized placebo-controlled trials comparing different progestins.

Results in Patients With Infertility

Pregnancy rates following MPA, lynestrenol or norethisterone acetate regimens vary from 5 to 90% depending on the stage of endometriosis and whether they were corrected or not. Timmonen and Johansson applied 5–10 mg lynestrenol daily and found 60% subjective improvement and 5% pregnancy rate only with a 40% failure and recurrence rate.[11] All these publications are observational or retrospective studies. There is no randomized controlled trial that has proven an improvement in fertility after any progestin medication.

A special place is proposed for dydrogesterone[29] in patients desiring pregnancy and suffering from endometriotic-related symptoms and bleeding problems. Because dydrogesterone does not inhibit ovulation it can be used for symptomatic treatment of pain and for reduction of bleeding problems. It can be used cyclically, has no androgenic side effects and is well tolerated. The studies used dydrogesterone in doses of between 10 and 60 mg/day, for various numbers of days per cycle, and were conducted over periods of 3–9 months. The majority of women became symptom-free or experienced a significant reduction in the number/severity of symptoms. These findings were supported by laparoscopic examination in several of the studies. Cyclic application of dydrogesterone has also been shown to induce regular menstruation with reduced blood loss and fewer days of bleeding, combined with excellent symptomatic relief, in women suffering from dysmenorrhea.[30–35] Table 1 summarizes the improvement in pain reported in these studies.

Side Effects

Negative side effects of progestins are disturbances of lipid and carbohydrate metabolism and the clotting system, more seen in C19-derivatives, as well as negative influences on mood swings and depression, more seen in C17-derivatives. Weight gain and bleeding problems are further causes for the cessation of long-term medication. The individual reactions to the progestins used differ depending on the type and dosage of the substance. For levonorgestrel, spotting, breakthrough bleeding, bloating, weight gain and headache was reported in up to a third of the patients;[36] for lynestrenol, hot flushes, acne and sweating were the main problems in up to 59%;[28] and for MPA spotting, bloating and weight gain occurred in almost two-thirds of treated women.[37] For dienogest, which was introduced in the European market last year, acne, hot flushes, headache, breast tenderness, loss of libido and fatigue are reported between 10 and 38%. The dosages used were 2 or 4 mg/day.[38]

Recurrence Rate

Only a few follow-up studies have been published concerning the recurrence rates after cessation of progestin medication. They reported a relatively high rate of recurrence of symptoms in the first year after the end of treatment (Table 2). Long-term follow-up shows recurrence rates above 50% in general.[5] Endometriosis is a chronic disease and progestins as well as other medical treatments will not eradicate the implants or cysts. Therefore, long-term medication is required, but no data are currently available for progestin therapy lasting longer than 6–12 months.

Inadequate data are available regarding the need for surgery for endometriosis subsequent to progestin therapy. More information is published concerning medication after surgery for the reduction of the recurrence rates, especially after surgical removal of ovarian endometrioma. Two observational studies[39,40] reported a significant reduction of ovarian endometriotic cyst recurrences after laparoscopic surgery using cyclic, low-dose, monophasic oral contraceptive pills and a recent prospective randomized study compared oral contraceptive pill cyclic use, continuous use and observation for 2 years after endoscopic cystectomy and found a significantly lower recurrence rate in continuous administration (8.2%) and cyclic use (14.7%), compared with 29% in the group of nonusers.[41]

Other Routes of Application

Depot injections of MPA are very effective in suppressing endometriosis-related complaints. A significant drawback to the use of depot preparations is the possible prolonged interval to resumption of ovulatory cycles after discontinuance. Therefore, this type of application is recommended only in elderly patients, who do not desire pregnancy.[1] The injectible depot MPA was as effective as a combination of oral contraceptive with low-dose danazol (50 mg/daily), but significantly more bleeding problems were observed in the MPA group.[37]

To reduce the adverse side effects of medical treatments, a new aspect is the intrauterine administration of progestogens, which can be an effective treatment of symptomatic endometriosis (Table 3). The C19 progestogen levonorgestrel is delivered directly in the uterine cavity with a rate of 20 µg/day during a period of 5 years. Data have been published showing positive effects on endometriosis-related pain and deep infiltrating endometriosis also.[42] Not only were the pain and bowel symptoms alleviated; in addition, the size of the nodules was reduced, as demonstrated with transrectal sonography. This is in contrast to the general opinion that deep infiltrating lesions are not responsive to medical therapy. A 3-year follow-up study found a pain-free continuation rate of 56% only for the levonorgestrel intrauterine device,[43] and a recent prospective randomized controlled trial demonstrated positive effects in progressed and severe endometriosis, but reduction of symptoms was higher in patients receiving GnRH analogs,[44] whereas other prospective randomized studies have been in favor of the local administration of levonorgestrel.[45,46] Irregular bleeding during the initial months of application were frequent side effects of the device, but by the end of the study 70% of the women were amenorrheic. In comparison, all GnRH analog users became amenorrheic in a shorter time.

A new approach to improve the use of progestins in endometriosis is the development of subcutaneous implants of MPA. There are two prospective randomized multicenter studies comparing the new progestin depot with the leuprolide depot.[47,48] No differences were observed in the reduction of pain symptoms, but demineralization of bone and hypoestrogenism side effects were found in the GnRH agonist group and bleeding problems were frequent in the MPA group.

It is necessary to mention one study including 100 patients with histologically proven endometriosis: MPA was tested against placebo in a double-blind randomized controlled trial. No differences were found in reducing pain symptoms or influencing the American Fertility Society scores at the second-look laparoscopy at the end of the 3-month period of medication.[49]

Putting the limited scientific data about effectivity and indications for progestins in case of endometriosis together, it is clear that there are, from a clinical point of view – symptomatic pain relief – no differences if sufficient dosages for suppression of the cycle and stopping the growth of the endometrium are used. Because endometriosis is a chronic disease, long-term medications or repeated medications are needed. Therefore, low-dose progestins alone or in combination with low-dose estrogen (to reduce bleeding problems) play an important role in the management of endometriosis-related symptoms, because their side effects are often tolerable, the metabolic disturbances are clinically unimportant and they are inexpensive.


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