Study of Dienogest For Dysmenorrhea and Pelvic Pain Associated With Endometriosis
Study of Dienogest For Dysmenorrhea and Pelvic Pain Associated With Endometriosis
Study of Dienogest For Dysmenorrhea and Pelvic Pain Associated With Endometriosis
Objective
To evaluate the effect of orally administered dienogest (DNG) for dysmenorrhea and pelvic pain associated with
endometriosis.
Methods
For this study we recruited 89 patients with dysmenorrhea and pelvic pain associated with endometriosis diagnosed by
laparoscopy. All patients complained of persistent dysmenorrhea and pelvic pain despite surgical treatment 6 months
previously. After 6 months of DNG treatment, we used a 0 to 3 point verbal rating scale to measure the severity of disability
in daily life due to dysmenorrhea and pelvic pain, and the use of analgesics. Weight gain, serum lipid and liver enzyme tests
were performed before treatment and after 6 months of DNG treatment.
Results
Total dysmenorrhea scores assessed by the verbal rating scale significantly decreased by the end of treatment (P<0.001).
The mean (±standard deviation) pain score for dysmenorrhea before and after treatment were 1.42±1.1 and 0.1±0.3,
respectively. The mean non-menstrual pelvic pain scores before and after treatment were 0.52±0.6 and 0.18±0.3,
respectively, showing a significant difference (P<0.001). The use of analgesics significantly decreased by the end of
the treatment (P<0.001). The associated adverse effects were weight gains (in 56 of 89 patients, 63%) and uterine
bleeding (in 28 of 89 patients, 31.5%). The weight gain (before treatment, 57.9±9.7; after treatment, 61.1±12.6) was
statistically significant (P<0.040).
Conclusion
This study demonstrated that orally administered DNG could be used to effectively treat dysmenorrhea and pelvic
pain associated with endometriosis although the side effects of weight gain and uterine bleeding should be
considered.
Keywords: Dienogest; Dysmenorrhea; Endometriosis
Introduction
Dysmenorrhea is the most common symptom in patients with
Received: 2016.2.29. Revised: 2016.6.13. Accepted: 2016.6.14.
endometriosis [1]. Endometriosis is defined as the presence Corresponding author: Hyuk Jung
of endometrial glands and stroma outside the uterus. It is a Department of Obstetrics and Gynecology, Chosun University School of
chronic gynecologic disease. Symptoms include chronic pelvic Medicine, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Korea
pain, dysmenorrhea, dyspareunia, and infertility in reproduc- Tel: +82-62-220-3091 Fax: +82-62-232-2310
E-mail: bimilo@hanmail.net
tive-age women. http://orcid.org/0000-0003-2237-2422
Current guidelines for the medical treatment of endome-
triosis recommend hormonal therapies that suppress ovarian Articles published in Obstet Gynecol Sci are open-access, distributed under the terms of
the Creative Commons Attribution Non-Commercial License (http://creativecommons.
function to decrease the serum estradiol concentration and org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution,
thus shrink the lesions. Gonadotropin-releasing hormone ago- and reproduction in any medium, provided the original work is properly cited.
nists (GnRH-a) are effective. Danazol, progestin, and estrogen/ Copyright © 2016 Korean Society of Obstetrics and Gynecology
506 www.ogscience.org
Soo Ah Kim, et al. DNG for dysmenorrheal and pelvic pain
progestin combinations are also used [2]. endometriosis. The institutional review board approved the
Although a GnRH-a exhibits considerable efficacy by de- study, and informed consent was obtained from all women.
creasing the serum estradiol concentration to postmenopaus-
al levels, such agents are accompanied by a high incidence 2. Patient monitoring
of hypoestrogenic symptoms, and their long-term use is as- Of those evaluated for DNG use were, 69 patients (78%) had
sociated with a substantial decrease in bone mineral density, recurrent pain despite 6 months of GnRH-a use after surgery,
limiting the duration of use [3]. 20 (22%) with recurrent pain had been diagnosed endome-
There is, therefore, a need for new and highly effective triosis prior to surgery. Treatment with DNG began on the 3rd
drugs that can be used over a longer term. The progestin day (±2 days) of the menstrual cycle and continued for 6 cy-
dienogest (DNG) was developed for oral contraception, en- cles. During the 2 menstrual cycles before starting the study,
dometriosis treatment, and menopause management. DNG each patient underwent a pre-recruitment evaluation, consist-
is a synthetic progestogen that acts as a specific progesterone ing of a general medical and gynecologic history, a physical
receptor agonist with anti-androgenic activity and strong oral and pelvic examination, a clinical evaluation of the signs and
endometrial activity [4]. symptoms, a patient evaluation of pain, and a review of the
DNG (Visanne, Bayer HealthCare, Berlin, Germany) is a menstrual record, including scoring of dysmenorrhea and
selective progestin that has recently been approved for the non-menstrual pain, and recording of details about the use of
treatment of endometriosis in Europe, Japan, and other coun- analgesics. The effect of treatment was evaluated at the final
tries, at a low oral dose of 2 mg/day. DNG reduces endome- visit after completing the treatment course.
triosis lesions by creating a local progestogenic environment, Patients included in the study had dysmenorrhea or pelvic
while only moderately suppressing systemic estrogen levels pain scoring higher than 3 points at the admission visit by us-
[5,6]. ing a modified pain scale originally developed by Biberoglu
Therefore, we performed a clinical trial to examine the ef- and Behrman [8] and Andersch and Milsom [9]. This verbal
fect of oral administration of 2 mg DNG on dysmenorrhea rating scale (VRS) defines pain according to limitations on
associated with endometriosis. The aim of this study was to the ability to work and the need for analgesics, based on the
determine the effects of DNG, and compare the results with number of days analgesics are used.
previous reports. The severity of dysmenorrhea and non-menstrual pelvic pain
was scored by using a scale ranging from 0 to 3 (0=no pain,
1=some loss of work (or study) efficiency, 2=need for some
Materials and methods rest, with loss of work, and 3=rest for more than 1 day); the
use of analgesics was similarly scored (0=none, 1=analgesic
1. Patient selection use for 1 day, 2=analgesic use for 2 days, and 3=analgesic
The study was conducted at the Department of Obstetrics use for >3 days).
and Gynecology at Chosun University Hospital. Between July Body weight was measured 6 months after treatment end-
2013 and July 2015, 105 reproductive-age women (range, ed with DNG. Serum lipids and liver enzyme tests were per-
22 to 53 years) who had endometriosis were enrolled in this formed before, and after 6 months of treatment with DNG.
non-randomized prospective study. Of 16 patients who did The adverse effects were investigated by questionnaire after
not completed the study, 9 were lost to follow up, 6 had the treatment ended. Weight gain was defined as an increase
inadequate charting, and 1 was excluded because of severe of over 1 kg, and uterine bleeding as bleeding more than 10
bleeding. Inclusion criteria included histologically-proven en- days.
dometriosis (stages I to IV, based on revised American Society
of Reproductive Medicine scoring) [7]. Exclusion criteria were 3. Statistical analysis
amenorrhea of 3 or more months, a need for primary surgical A paired t-test was used to compare changes in dysmenor-
treatment of endometriosis, use of hormonal agents within 1 rhea, and non-menstrual pelvic pain scores, use of analgesics,
to 6 months of screening (depending on the class of agent) or weight, serum lipid, and liver enzyme levels before and after
abnormal findings on gynecological examination other than treatment with DNG. A P-value of <0.05 indicated statistical
www.ogscience.org 507
Vol. 59, No. 6, 2016
508 www.ogscience.org
Soo Ah Kim, et al. DNG for dysmenorrheal and pelvic pain
ever, most have symptoms different intensity. The major the end of treatment, as seen in our study. Several clinical
symptoms are dysmenorrhea, chronic pelvic pain, and deep trials have shown that contraceptive pills containing DNG
dyspareunia [10]. This study demonstrated that DNG was provide good cycle control, with shorter and lighter bleeding
effective in decreasing endometriosis symptom scores. Sev- than other contraceptives [17,18]. At the same DNG dose (2
eral progestins and synthetic steroids such as drospirenone, mg/day), the choice of contraceptive can have a significant in-
trimegestone, nestorone, nomegestrol acetate, and DNG, fluence on the incidence rate of irregular vaginal bleeding [19].
which mimic the action of endogenous progesterone, have The incidence rate of irregular bleeding in our study (28 of
been developed for use as contraceptives and in hormone 89, 31.5%) was less than that (61.6%) reported for DNG in
replacement therapy, and for treatment of gynecological dis- another study, in which the patients were prescribed DNG,
ease, such as endometriosis [11]. DNG was approved for the 1 mg orally twice a day for 16 weeks [19]. The incidence of
treatment of endometriosis in the EU (as Visanne) in Decem- genital bleeding decreased with continued treatment and
ber 2009. It was also approved in Japan (as Dinagest 1 mg) resolved by the end of treatment in our study. When uterine
in October 2007. Harada et al. [12] demonstrated that DNG bleeding persisted for more than 10 days of DNG treatment,
is as effective as a GnRH-a for relieving the pain associated the medication was discontinued. After the uterine bleeding
with endometriosis, but with a significantly lower decrease in had completely dissolved DNG treatment was resumed, after
bone mineral density and fewer hot flushes, which are typical which the cycle was maintained with no uterine bleeding.
side-effects of a GnRH-a. However, it is known that irregular The selective steroid receptor activities of DNG lead to fewer
genital bleeding occurs more frequently with DNG than with adverse effects, such as hirsutism, acne, weight gain, unfavor-
a GnRH-a. able carbohydrate and lipid metabolism compared to previous
Although laparoscopic diagnosis and treatment for endo- synthetic progestins, such as medroxyprogesterone acetate or
metriosis are currently used worldwide, Alkatout et al. [13] norethisterone [6].
showed that combined surgical and hormone therapy (3.75 The data in the present study showed weight increase by
mg GnRH-a, monthly for 3 months) for endometriosis was the end of treatment. A previous paper reported that the
the most effective treatment, especially for the reduction of absence of weight gain with DNG, but the present study
symptoms (dysmenorrhea, pelvic pain, and others). showed a statistically significant difference (P<0.040).
The present study also used combined surgical and hormone Clinical evidence for the efficacy of DNG is lacking. Our
therapy, but with a difference. DNG, which may be used for 1 results demonstrated that oral administration of 2 mg DNG
year or more [13,14], was used instead of a GnRH-a which has effectively decreased dysmenorrhea associated with endo-
a limited duration of use, as it decreases bone mineral density. metriosis. No serious adverse events were observed. Data
A comparative trial of DNG (2 mg/day) versus a GnRH-a [15,16] from long-term studies indicated that pain relief continued to
concluded that DNG is as effective for the relief of pain associ- improve with sustained DNG therapy for 1 year and beyond
ated with endometriosis [15]. The proportion of women free of [14,20]. DNG can also induce decidualization of ectopic en-
pelvic pain and dysmenorrhea at 24 weeks was approximately dometrial tissue and atrophy of lesions with continued treat-
60% in both treatment arms: 82% in the DNG group and ment by creating a hypoestrogenic and hyperprogestogenic
90% in the GnRH-a group, respectively [16]. endocrine environment; thus, DNG is effective in treating
Various adverse effects of hormone therapy for the treat- endometriosis at a dose of 2 mg daily [6]. Our results sup-
ment of endometriosis have been reported, including uterine port the common clinical practice of treating dysmenorrhea
bleeding, weight gain, headache, nausea, and hot flushes. resulting from endometriosis with oral administration of 2 mg
In this study, patients complained of weight gain, uterine DNG. This study demonstrated that DNG was effective in de-
bleeding, fatigue, insomnia, breast tenderness, depression, creasing the scores of all endometriosis symptoms by the end
dizziness, and other symptoms (Table 3). The most common of treatment.
adverse effects were uterine bleeding and weight gain. In conclusion, the present study clearly demonstrated that
Horie et al. [15] reported rates of genital bleeding in DNG orally administered DNG can be used to effectively treat dys-
and GnRH-a groups of 122 of 129 (95%) and 85 of 126 menorrhea and pelvic pain associated with endometriosis,
(67%), respectively. However, this adverse effect resolved by although the side effects of weight gain and uterine bleeding
www.ogscience.org 509
Vol. 59, No. 6, 2016
should be considered. DNG is effective for pain control, the therapy in endometriosis: short-term and long-term ef-
main focus of treatment for endometriosis. Despite its effec- fectiveness. Am J Obstet Gynecol 1981;139:645-54.
tiveness, there were a few limitations. Previously unreported 9. Andersch B, Milsom I. An epidemiologic study of young
weight gain was statistically meaningful, but the effect of women with dysmenorrhea. Am J Obstet Gynecol
long-term treatment for more than 6 months is unknown. 1982;144:655-60.
10. Petta CA, Matos AM, Bahamondes L, Faundes D. Cur-
rent practice in the management of symptoms of endo-
Conflict of interest metriosis: a survey of Brazilian gynecologists. Rev Assoc
Med Bras (1992) 2007;53:525-9.
No potential conflict of interest relevant to this article was 11. Sitruk-Ware R. New progestogens: a review of their ef-
reported. fects in perimenopausal and postmenopausal women.
Drugs Aging 2004;21:865-83.
12. Harada T, Momoeda M, Taketani Y, Aso T, Fukunaga M,
Acknowledgments Hagino H, et al. Dienogest is as effective as intranasal
buserelin acetate for the relief of pain symptoms associ-
This study was supported by a research fund from Chosun ated with endometriosis: a randomized, double-blind,
University, 2014. multicenter, controlled trial. Fertil Steril 2009;91:675-81.
13. Alkatout I, Mettler L, Beteta C, Hedderich J, Jonat W,
Schollmeyer T, et al. Combined surgical and hormone
References therapy for endometriosis is the most effective treat-
ment: prospective, randomized, controlled trial. J Minim
1. Harada T, Momoeda M, Taketani Y, Hoshiai H, Terakawa Invasive Gynecol 2013;20:473-81.
N. Low-dose oral contraceptive pill for dysmenorrhea as- 14. Dallenbach-Hellweg G. The influence of contraceptive
sociated with endometriosis: a placebo-controlled, dou- steroids on the histological appearance of the endo-
ble-blind, randomized trial. Fertil Steril 2008;90:1583-8. metrium. In: Diczfalusy E, Fraser IS, Webb FT, editors.
2. Olive DL, Pritts EA. Treatment of endometriosis. N Engl J Endometrial bleeding and steroidal contraception. Bath:
Med 2001;345:266-75. Pitman Press; 1980. p.153-73.
3. Crosignani P, Olive D, Bergqvist A, Luciano A. Advances 15. Horie S, Harada T, Mitsunari M, Taniguchi F, Iwabe T, Ter-
in the management of endometriosis: an update for cli- akawa N. Progesterone and progestational compounds
nicians. Hum Reprod Update 2006;12:179-89. attenuate tumor necrosis factor alpha-induced interleu-
4. Sasagawa S, Shimizu Y, Kami H, Takeuchi T, Mita S, Ima- kin-8 production via nuclear factor kappa B inactivation in
da K, et al. Dienogest is a selective progesterone recep- endometriotic stromal cells. Fertil Steril 2005;83:1530-5.
tor agonist in transactivation analysis with potent oral 16. Strowitzki T, Marr J, Gerlinger C, Faustmann T, Seitz C.
endometrial activity due to its efficient pharmacokinetic Detailed analysis of a randomized, multicenter, com-
profile. Steroids 2008;73:222-31. parative trial of dienogest versus leuprolide acetate in
5. Oettel M, Breitbarth H, Elger W, Graser T, Hubler D, endometriosis. Int J Gynaecol Obstet 2012;117:228-33.
Kaufmann G, et al. The pharmacological profile of dien- 17. Zeun S, Lu M, Uddin A, Zeiler B, Morrison D, Blode H.
ogest. Eur J Contracept Reprod Health Care 1999;4(Sup- Pharmacokinetics of an oral contraceptive containing
pl 1):2-13. oestradiol valerate and dienogest. Eur J Contracept Re-
6. McCormack PL. Dienogest: a review of its use in the prod Health Care 2009;14:221-32.
treatment of endometriosis. Drugs 2010;70:2073-88. 18. Endrikat J, Parke S, Trummer D, Schmidt W, Duijkers I,
7. Revised American Society for Reproductive Medi- Klipping C. Ovulation inhibition with four variations of
cine classification of endometriosis: 1996. Fertil Steril a four-phasic estradiol valerate/dienogest combined oral
1997;67:817-21. contraceptive: results of two prospective, randomized,
8. Biberoglu KO, Behrman SJ. Dosage aspects of danazol open-label studies. Contraception 2008;78:218-25.
510 www.ogscience.org
Soo Ah Kim, et al. DNG for dysmenorrheal and pelvic pain
19. Cosson M, Querleu D, Donnez J, Madelenat P, Konincks ized study. Fertil Steril 2002;77:684-92.
P, Audebert A, et al. Dienogest is as effective as triptore- 20. Fraser IS. Bleeding arising from the use of exogenous
lin in the treatment of endometriosis after laparoscopic steroids. Baillieres Best Pract Res Clin Obstet Gynaecol
surgery: results of a prospective, multicenter, random- 1999;13:203-22.
www.ogscience.org 511