The place of dydrogesterone in the treatment of endometriosis and adenomyosis

Maturitas 65S (2009) S23–S27

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The place of dydrogesterone in the treatment of endometriosis and adenomyosis Karl-Werner Schweppe ∗ Department of Obstetrics and Gynecology, Ammerland Clinic GmbH, Academic Teaching Hospital of the University of Göttingen, Lange Strasse 28/D-26655 Westerstede, Germany

a r t i c l e

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Article history: Received 15 September 2009 Received in revised form 9 November 2009 Accepted 9 November 2009

Keywords: Endometriosis Adenomyosis Progestins Dydrogesterone Bleeding disorders

a b s t r a c t Oral progestins have been reported to be effective in the treatment of endometriosis. The mode of action is still a matter of debate, but it may involve modulation of mitotic activity, local growth factors and growth factor receptors, as well as other paracrine mechanisms and anti-inflammatory reactions. Other treatments such as danazol and GnRH-agonists are effective with regard to relief of symptoms and regression of the endometriotic implants, but are associated with high recurrence rates and a wide range of side effects. Progestins are therefore indicated in the symptomatic management of pain, bleeding disorders and other symptoms caused by endometriosis when long-term medication or repeated courses of treatment are indicated. The relationship between costs and efficacy is good, and the side effects are tolerable in most cases. Dydrogesterone is particularly suitable in cases where the woman desires to become pregnant and to prevent bleeding problems. Only very limited data are available concerning the use of progestins in adenomyosis and no conclusions can be drawn. © 2009 Elsevier Ireland Ltd. All rights reserved.

1. Endometriosis

2. Effects on target tissue

Oral progestins without an estrogen component were first reported to be effective in the treatment of endometriosis more than 40 years ago. Various progestins have been used, including derivatives of natural progesterone (e.g. dydrogesterone, medroxyprogesterone acetate [MPA]) and C-19-nortestosterone derivatives (e.g. norethisterone, lynestrenol, desogestrel), which have different profiles regarding their potency on the hypothalamicpituitary axis, their metabolic processes, and their effects on breast tissue and genital organs. The secretory transformation of estrogen-primed uterine endometrium is their common characteristic, an effect for which different dosages are necessary. Progestins reduce the frequency and increase the amplitude of pulsatile gonadotropin-releasing hormone (GnRH) release, which results in a reduction of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion. With the exception of dydrogesterone, continuous application therefore leads to a suppression of ovarian steroidogenesis with anovulation and low serum levels of ovarian steroids. This hypoestrogenic status causes decidual transformation of the eutopic endometrium and also, to some degree, of ectopic lesions. However, in order to induce decidual transformation with resultant necrosis and resorption of the implant, a concomitant estrogen effect is required [1]. As continuous progestin therapy results in low serum estradiol levels, breakthrough bleeding is common.

The mode of action of progestins on the endometriotic implant is still a matter of debate. Early studies postulated that the effects were mediated via steroid receptor mechanisms, as observed in the uterine mucosa. Only one study was published, which examined the morphological features of endometriotic implants in 18 patients after treatment with dydrogesterone 20 mg/day for 2–5 months or 60 mg/day for 2 months [2]. Secretory changes in the glands and decidualisation of the stroma were judged as no response in 4 cases; the remaining 14 cases were considered to have had a moderate or good response as shown by a lack of growth and secretion within the ectopic foci (with or without involutionary changes). Later studies, however, raised some doubts about this hypothesis. Endometriotic foci contain only very low, or even non-existent, levels of progesterone receptors [3], and enzyme systems differ widely between eutopic and ectopic endometrial tissues [4]. Progestins reduce the synthesis of their own receptors, which results in diminished sensitivity of the implants during long-term treatment. Morphological studies have revealed different effects after long-term (9 months) progestin treatment, with some implants remaining unchanged, some showing arrested epithelium and some having abortive secretory reactions, although decidual reactions and necrosis were not observed [5]. Comparative ultrastructural examinations between eutopic and ectopic endometrium have also revealed significant differences during the menstrual cycle; changes in the endometriotic foci appear to be delayed compared with the uterine endometrium, with the foci remaining proliferative in the luteal phase [6]. This insensitivity to the influence of progestins (so called progesterone blockage) may

∗ Tel.: +49 4488 503230; fax: +49 4488 503999. E-mail address: [email protected]. 0378-5122/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2009.11.011

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Figure 1. Influence of progestins on TNF-alpha and interleukin-8-induced inflammatory reactions in lymphocytes and proliferation of endometriotic stroma cells [9,10].

be caused by specific changes in enzyme systems [7], in addition to low or reduced receptor concentrations. The enzyme 17␤hydroxysteroid-dehydrogenase type 2 is lacking in endometriotic foci and cannot be activated by progestins. This results in permanent increased proliferation during the menstrual cycle as estradiol is not inactivated [8]. In addition, there is disruption of aromatase activity in ectopic implants. Thus, more estradiol is produced by the endometriotic foci in the conversion of androgens to estrogens. Inflammatory reactions caused by endometriotic implants are significant in disease progression and cause pain symptoms. An anti-inflammatory mechanism by which the growth of endometriosis is controlled by progesterone and progestins has recently been proposed by Horie et al. [9]. Tumor necrosis factor (TNF)-alpha and estradiol induce the proliferation of endometriotic stroma cells via nuclear factor (NF)-kappa-␤, whereas progestins reduce TNF-alpha-induced NF-kappa-␤ activation (Fig. 1). Dydrogesterone has also been shown to modulate immune responses via suppression of interleukin (IL)-8 production in lymphocytes [10]. The increase in nitric oxide production seen with dydrogesterone may also play an important anti-inflammatory role [11]. To date, details regarding the mechanism of action and the morphological changes induced by progestins are only partly understood. Moreover, it remains unclear as to whether the mode of action varies between the different types of progestins.

3. Clinical experiences Oral administration of various progestins in low dosages (5–60 mg/day) has been shown to have a range of beneficial effects. In general, these results do not differ considerably from those achieved with combined estrogen–progestin therapy (i.e. continuous oral contraceptives). However, progestins have an advantage over combined treatment in that they avoid estrogen-induced side effects. These mainly constitute spotting and bleeding problems, which may be managed by increasing the dosages, giving additional estrogen medication or interruption of treatment for 5–7 days.

Dydrogesterone was first reported to be effective in endometriosis in the 1960s [12]. In this small study involving 13 patients, some improvement was reported in 70% of women. Overall success rates of around 90% were also reported in other small studies and clinical case reports [13–16]. The most important studies assessing the use of oral dydrogesterone for the management of endometriosis are summarized in Table 1 [17–23]. These studies used dydrogesterone at 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. Laparoscopic examination in several of the studies supported these findings. 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 [24–29]. Table 2 summarizes the improvement in pain reported in these studies. Other oral progestins have also been evaluated in women with endometriosis. For example, dienogest 2 mg/day resulted in a significant reduction in endometriosis-related pain [30]. However, spotting was reported in 95% of cases, and this persisted in 60% of women even with increased dosages of 4 and 6 mg/day. In the same study, norethisterone acetate 10 mg/day was associated with breakthrough bleeding and spotting in 25% of women. In a randomized trial of MPA, Telimaa et al. [31] reported a 50% regression rate of ectopic implants and 13% partial regression with scar formation in the treatment group compared with rates of 12% and 6%, respectively, in the placebo group. Similar results were demonstrated in a randomized study comparing high dose medrogestone with danazol [32]. Depot injections are an alternative to oral administration. Intramuscular and subcutaneous injections of MPA given every 3 months have been shown to be very effective in suppressing the signs and symptoms of endometriosis [33–35]. However, a significant drawback to the use of depot preparations is the occasionally prolonged interval to resumption of ovulatory cycles after treatment discontinuation. This mode of administration is therefore

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Table 1 Dydrogesterone in the management of endometriosis. Reference

N

Study design

Treatment

Results

Overton et al. [20]

62

Double-blind, prospective, randomized, placebo-controlled

Placebo, Dydrogesterone 40 or 60 mg/day for 12 days/cycle for 6 months

Open, prospective, controlled

Pregnancy rates 37%, 48% and 50%; pain-free 47%, 43% and 64%; improvement/no change in AFS score in 73%, 64% and 70% Pregnancy rates 30%, 63%, 46%, 50% and 35%; reduction in pain 20%, 90%, 72%, 80% and 63%

Makhmudova et al. [22]

300

Walker [18]

14

Open, prospective, baseline placebo-controlled

Placebo, Danazol 800 mg/day, Norclut 10 mg/day, Dydrogesterone 10 mg/day on days 5–25, Depot MPA 50 mg/week for 6 months Dydrogesterone 30 mg/day on days 5–25 for 6 cycles

Johnston [17]

49

Open, prospective, baseline-controlled

Dydrogesterone 10 mg/day for 9 months

Kaiser and Wagner [19]

20

Open, prospective, baseline-controlled

Dydrogesterone 10 mg/day on days 5–15 and 20 mg/day on days 16–25 for 6–9 months

Tumasian et al. [21]

16

Trivedi et al. [23]

98

Open, prospective, baseline-controlled Open, prospective, baseline-controlled

Dydrogesterone 10 mg/day on days 5–25 for 6 cycles Dydrogesterone 10 or 20 mg/day on days 5–25 for 3–6 cycles

6/14 had significant improvement in pain symptoms; 5/14 showed laparoscopic improvement 89% pain-free; 53% pregnancy rate; of 32 patients who underwent laparoscopy, 21 were cured, 9 had regression and 2 were unchanged 30% symptom-free and 60% improved; laparoscopically confirmed elimination in 75% and improvement in 20% Pregnancy rate 50% Reduction in pelvic pain, dysmenorrhea and dyspareunia was 95%, 87% and 85%. 21% of patients considered cured and 67% showed improvement

AFS: American Fertility Society.

only recommended for older women who do not wish to become pregnant [32]. Another option is the intra-uterine administration of progestins [36,37]. A 3-year follow-up study reported significant reductions in pain and blood loss with the levonorgestrel intra-uterine device, with 56% of women continuing treatment for the full 3 years [36]. Inadequate data are available regarding the need for surgery for endometriosis subsequent to progestin therapy. There are only a few randomized studies in the literature comparing GnRH analogs with low dose progestins. Vercellini et al. [38] compared ethinylestradiol 0.02 mg/day plus desogestrel 0.15 mg/day versus goserelin 3.6 mg monthly. They reported a significant reduction of deep dyspareunia and cyclic pain in both groups, with goserelin being superior to the oral contraceptive on a linear analog scale assessment. Non-menstrual pain was diminished, without differences between the treatments. Regidor et al. [39] compared lynestrenol 5 mg/day with leuprorelin 3.7 mg monthly. Using repeat laparoscopy, they found a significantly

greater reduction of endometriotic implants in the leuprorelin group (reduction in the revised 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). The improvement in symptoms such as chronic pelvic pain and dyspareunia did not differ significantly between the groups. The authors concluded that medication with GnRH-agonists is indicated in the first instance, but that secondary progestins are very useful for long-term treatment or repeated medication. A recent study reported that oral dienogest 2 mg/day was equally as effective as intranasal buserelin 900 ␮g/day in terms of subjective symptoms of pain and the objective finding regarding limited uterine mobility [40]. However, the reduction in the objective parameter induration in the pouch of Douglas was greater with buserelin. Because endometriosis is associated with reduced fertility, pregnancy rates are a good surrogate parameter for the efficacy of medical or surgical treatment. Pregnancy rates following treatment with different progestins vary considerably depending on the

Table 2 Dydrogesterone in the management of dysmenorrhea. Reference

N

Study design

Treatment

Results

Aydar and Coleman [26]

50

Double-blind, prospective, randomized, placebo-controlled

Dydrogesterone 10 mg/day or placebo on days 5–25 for 6 months

Fairweather [25]

50

Dydrogesterone 5 mg/day or placebo on days 5–25 for 5 months

Schellen and Wesselius de Casparis [27]

46

Double-blind, prospective, cross-over, placebo and no treatment controlled Double-blind, prospective, cross-over, placebo-controlled

Dydrogesterone 5 mg/day or placebo on days 5–25 for 4 months

Double-blind, prospective, cross-over, placebo-controlled

Dydrogesterone 10 mg/day or placebo on days 5–25 for 4 months

Open, prospective, baseline-controlled Open, prospective

Dydrogesterone 20 mg/day on days 5–25 for 3 months Dydrogesterone 10 or 15 mg/day on days 5–25 for 2 months

Improvement in 17/25 (60%) given dydrogesterone and 2/25 (8%) given placebo Improvement in 15/25 (60%) given dydrogesterone and 7/25 (30%) given placebo Improvement in 11/23 (47%) given dydrogesterone and 3/23 (13%) given placebo Use of analgesics significantly reduced with dydrogesterone but not placebo Improvement in 62/65 (95%)

Gould [28]

340

Ohlenroth and Hatzmann [29]

67

Bishop [24]

64

19/30 (63%) pain-free with 10 mg/day and 28/34 (83%) with 15 mg/day

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stage of endometriosis, additional infertility factors and whether or not these have been treated. Makhmudova et al. [22] reported a pregnancy rate of 50% with dydrogesterone compared with 35% with depot MPA and 30% with placebo. Timmonen and Johansson [41] found a 60% subjective improvement rate with lynestrenol 5–10 mg/day, but only a 5% pregnancy rate and a 40% failure and recurrence rate. Although only a few follow-up studies have been published, there appears to be a relatively high rate of symptom recurrence after discontinuation of treatment; recurrence rates of ≥50% have been reported 6 months after stopping treatment [6]. Long-term treatment may be necessary and must therefore be well tolerated. The tolerability of danazol, the use of which is limited by the occurrence of androgenic side effects [42], and GnRH analogs, which cause vasomotor symptoms and bone loss, may not be adequate for such long-term use. The side effects of progestins include disturbances in lipid- and carbohydrate-metabolism and clotting systems, as well as mood swings and depression. Weight gain and bleeding problems may also discourage women from using progestins long-term. This is true for the C17 progestins and especially the C19 derivatives. In contrast, dydrogesterone appears to be particularly well tolerated [22,43]. Putting together the limited data concerning the efficacy of dydrogesterone and other progestins in endometriosis, it is clear that there is no place for progestin medication in cases of severe endometriosis with or without infertility. The treatment of choice in this situation is endoscopic surgery, possibly combined with in vitro fertilization. However, there is a place for low dose progestins alone, or in combination with low dose estrogen, in the management of endometriosis-related symptoms in the early stages, despite the fact that the endometriotic implant itself is resistant to the effects of progestins, or after surgical treatment to reduce the risk of recurrence.

has no androgenic side effects and ovulation is not inhibited. Indeed, because endometriosis is a chronic disease that necessitates long-term or intermittent repeated medication, and progestins are relatively well tolerated and inexpensive [49], there could well be a renaissance of these drugs in the treatment of endometriosisrelated symptoms. Randomized, controlled trials are, however, necessary to clarify the duration of treatment, the type of progestin, the dosage, the use of intermittent medication and the potential for combination with other drugs that are effective in the management of endometriosis. 5. Adenomyosis The treatments used in adenomyosis are the same as those used for endometriosis [50], but only very limited data are available concerning their effects. Whereas endometriosis can be diagnosed by laparoscopy and biopsy, adenomyosis is frequently not diagnosed until after hysterectomy. However, magnetic resonance imaging, high resolution vaginal sonography and uterine biopsy are all modern methods that can help to improve its early detection. Medication may be effective in controlling the symptoms of adenomyosis, such as bleeding disorders, dysmenorrhea and lower abdominal pain. Nevertheless, the frequent coexistence with endometriosis and the similarity of symptoms, together with the lack of controlled studies, make it impossible to quantify the efficacy of different drugs on adenomyosis. Contributor Karl-Werner Schweppe is the sole contributor. Competing interest There is no actual or potential conflict of interest.

4. Conclusions Acknowledgement During the last 30 years, new effective medications have been introduced for the treatment of endometriosis, and GnRH analogs have become the standard drug in the management of endometriosis [44]. There has therefore been a paucity of scientific interest in progestins in recent years. In a review of the literature, Vercellini et al. [45] identified only four randomized controlled trials, and these included a very limited number of patients. Nevertheless, these studies confirmed the beneficial effect of progestins for the treatment of endometriosis-related complains. The same group performed a follow-up review of the literature between 1993 and 2003 and found a small number of more recent studies [46]; however, the authors acknowledged that the aim was not to provide a qualitative and quantitative analysis of comparative trials and the methodological quality was not considered in detail. A Cochrane review of progestogens and anti-progestogens for pain associated with endometriosis published in 2000 identified seven studies that were appropriate for inclusion, only three of which evaluated progestogens [47]. Finally, a systematic review of all the medical treatment options for endometriosis conducted in 2004 concluded that a meta-analysis was not possible as there was too much heterogeneity between the studies regarding protocols and inclusion/exclusion criteria, as well as the drugs and dosages selected [48]. Despite this, progestins have their place today in the symptomatic management of pain and other symptoms caused by endometriosis, when long-term medication is indicated, or when repeated courses of treatment are acceptable. Dydrogesterone is preferable in cases where the woman desires to become pregnant and to prevent bleeding problems, as it can be used cyclically,

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