Does Dienogest Increase the Risk for Repeat Endometriosis Surgery?

A recent study [2] has sparked discussions within the endometriosis community. The headline on reads “Dienogest Treatment Increases the Risk of Endometriosis Reoperation Rate.” This title implies that a Korean study has established a link between Dienogest use and a higher risk of reoperation.

However, we aim to delve deeper into the study’s findings to gain a clearer understanding.

In a Nutshell

  • The article on misinterprets the study in its headline.
  • The study’s significance is limited.
  • While the Dienogest group in the study experienced more reoperations than the non-Dienogest group, THERE ARE KEY CONSIDERATIONS:
  • The Korean study was retrospective, introducing numerous unknown variables that complicate establishing causality.
  • Elevated surgery rates were observed in women receiving Dienogest more than 9 months after GnRH therapy completion, rather than those receiving it earlier.
  • It is plausible that delayed Dienogest use could correlate with more severe recurring endometriosis symptoms, which in turn may lead to increased surgery rates.
  • Conversely, recurrence could have prompted Dienogest therapy.
  • Notably, substantial studies validating the effects of Dienogest are acknowledged in German guidelines.
  • The study focused on patients meeting the criterion of prior GnRH analog therapy, which is now less common in Germany.
  • Additional research is indispensable for a comprehensive perspective!
  • Ceasing Dienogest without medical consultation is strongly discouraged. Hormone therapies necessitate a personalized assessment of both advantages and drawbacks. Individual contexts should guide decisions.

What is the Study About?

The study conducted by Korean researchers from Inje University and Kyungpook National University focused on analyzing data from the Korean Health Insurance Fund.

The study included individuals who met the following criteria:

  • Diagnosed with any type of endometriosis, encompassing conditions like adenomyosis, endometrioma, and cases involving all layers.
  • Underwent at least one surgical procedure.
  • Received GnRH analog therapy.
  • Were covered by insurance between 2013 and 2017 with Dienogest entering the market in South Korea in 2013.

The study divided participants into two distinct groups:

  • Dienogest Group: This group consisted of women who received Dienogest therapy at some point after undergoing GnRH analog therapy.
  • No Dienogest Group: This group included women who did not receive Dienogest treatment.

Within the group of women who received Dienogest therapy during the observation period, a higher number of re-operations were noted.

The central question revolves around whether it can be concluded that taking Dienogest increases the likelihood of requiring another surgery.

From Sharks and Ice Cream

The study’s retrospective nature immediately draws attention. Analyzing past data seems logical, yet complications arise when isolated historical data lacks the ability to consider crucial influencing factors.

To elaborate, consider the analogy below:

Imagine examining data from Sydney, correlating shark bite rates with ice cream consumption. It might appear that more shark bites coincide with increased ice cream consumption, even suggesting that consuming ice cream attracts shark attacks. But intuitively, we would hesitate to conclude such a link, right?

While a higher incidence of shark bites may align with greater ice cream consumption, causality is not straightforward. The surge in ice cream consumption could align with warmer temperatures, leading to more beachgoers, surfers hitting the waves, and subsequently more shark encounters. Ice cream does not trigger shark bites; a deeper influence is at play.

In retrospective studies, this complexity persists. Concluding that Dienogest directly heightens reoperation risk is akin to mistaking ice cream for a shark attractant. The design inherently hinders deriving definitive cause-and-effect relationships.

Retrospective data unveils co-occurrences, not causation. Yes, those on Dienogest faced more reoperations, but asserting Dienogest’s direct causative role requires caution. Just as ice cream consumption is not to blame for shark bites, Dienogest is not definitively responsible for reoperations.

Deeper scrutiny unveils subtler correlations, more akin to the summer driving both ice cream consumption and shark interactions. Within the study, grasping these underlying connections is pivotal—identifying the “summer factor” in the Dienogest scenario.

Deep Dive into the Data and a Theory – Unveiling the Reasons for Dienogest Use

A meticulous analysis of the data reveals a key distinction: not all women began Dienogest treatment simultaneously. On average, it commenced approximately 100 days after GnRH analog therapy. The initiation varied, with some starting immediately, while others waited 6, 12, or even more months post-GnRH analog therapy completion.

From a clinical standpoint, two primary scenarios emerge for Dienogest prescription: prophylaxis against relapse or addressing recurrent symptoms.

Hence, the re-prescription of Dienogest can be attributed to one of three motives:

  • Standard Therapeutic Approach: Immediate prescription post-GnRH analog therapy.
  • Elevated Relapse Risk: Immediate prescription post-GnRH analog therapy due to heightened recurrence risk.
  • Symptoms Recurrence: Prescription upon symptoms reappearance, likely occurring later, potentially after 6 months to a year.

Reason 2 or 3 inherently signify an increased reoperation risk, motivating Dienogest use as a countermeasure.

Upon closer scrutiny, a pattern emerges:

  • Women receiving Dienogest within the initial 9 months post-GnRH analog therapy (possibly reasons 1 or 2) exhibited either fewer reoperations or similar frequencies.
  • Conversely, those receiving Dienogest 9 months after GnRH analog therapy or later witnessed a notable surge in surgeries (evidenced by significantly higher hazard ratios) compared to non-Dienogest counterparts.

One plausible explanation surfaces: this latter group likely received Dienogest due to recurring symptoms. If the Dienogest treatment inadequately managed those, subsequent surgery might have been inevitable.

It is a theory – an interpretation rather than a definitive explanation. The data does not distinctly elucidate why these women exhibited a heightened surgery likelihood.

Other Study Limitations

Within the study, the authors themselves acknowledge additional constraints:

The study lacked insight into symptoms, reasons for surgery, and various influential factors like the use of other contraceptives, pregnancies, and detailed surgery specifics. Consequently, the impact of these variables remains unexplored.

  • The study exclusively focused on women post GnRH analog therapy, a less common approach in Germany.
  • Women on Dienogest might have frequented medical appointments more, potentially prompting earlier surgeries.
  • The duration of Dienogest use varied, sometimes spanning only a few months.

Does this render the study flawed?

Retrospective studies hold significance; they unveil intriguing correlations that fuel further inquiry—then undertaken through planned and prospective research.

While this study bears limitations and imperfections, its existence serves a purpose. Published in a peer-reviewed journal, it serves as a foundation for constructing future theories. For instance, the authors dissect data to determine when Dienogest usage post-GnRH analogs might be reasonable or not. This insight lays the groundwork for prospective studies.

Designing a Study to Examine the Dienogest-Reoperation Relationship

To robustly examine the link between Dienogest and reoperation rates and to establish conclusive evidence, a well-designed confirmatory study should encompass the following characteristics:

  1. Prospective Nature: The study should be planned and outlined before data collection. This approach ensures preemptive identification and control of influential factors, thus promoting equal treatment across groups.
  2. Treatment Definition: Precise criteria for Dienogest administration need establishment. Factors such as timing (e.g., immediately after surgery or post-GnRH analog therapy), and targeted patient groups need to be explicitly defined.
  3. Group Definitions: The study should exclude or adjust for other variables that might influence outcomes, thus isolating the Dienogest effect.
  4. Randomized Control: Random allocation of participants to treatment and control groups minimizes bias and enhances reliability.
  5. Blinding: Employing a placebo in the control group mitigates bias even further.

In summary, the goal is to minimize confounding variables and achieve a clear understanding of Dienogest’s role in reoperation risk reduction. This approach is unattainable in retrospective studies, reinforcing the need for a meticulously designed prospective study.

Understanding the limitations of retrospective studies, one should approach their findings cautiously. Generalizations from such studies are limited, as variables often cannot be fully controlled.

Looking at the broader landscape of research, multiple studies together provide a more comprehensive perspective. For instance, a randomized controlled trial demonstrated Dienogest’s reoperation risk reduction similar to GnRH analogs [3]. Furthermore, a 2020 meta-analysis found Dienogest to significantly reduce endometriosis surgery recurrence risk [4].

Informed by current research, the guideline “Diagnostics and Therapy of Endometriosis” [1] recommends Dienogest usage for symptom control and recurrence prevention in Germany. Alternative options exist, like other progestogens and combined pills, with personalized discussions between patients and physicians being pivotal.

Conclusions from the Study [2]:

  1. The study highlights that women in the Korean group who received Dienogest 9 months or later post-GnRH analog therapy faced higher reoperation rates than those who received it immediately or not at all. However, causality is not definitive, and factors influencing Dienogest prescription remain unknown.
  2. It is crucial to acknowledge that drawing direct cause-and-effect relationships from this study is premature.
  3. Given the existing body of research, Dienogest has shown efficacy in symptom control and surgery recurrence prevention.
  4. Continued investigation into endometriosis and Dienogest therapy remains necessary.

Hormone therapy, including Dienogest, necessitates individual discussions with healthcare professionals. While guidelines might recommend Dienogest in specific contexts, ongoing assessment of benefits, risks, and side effects with physicians ensures optimal decision-making aligned with each patient’s unique situation.


  1. S2K Guideline 015/045 – Diagnosis and Therapy of Endometriosis of 2020 (AWMF)
  2. Seo YS, Yuk JS, Cho YK, Shin JY. Dienogest and the Risk of Reoperation in Endometriosis. J Pers Med. 2021 Sep 17;11(9):924. doi: 10.3390/jpm11090924. PMID: 34575701; PMCID: PMC8470369.
  3. Takaesu Y, Nishi H, Kojima J, Sasaki T, Nagamitsu Y, Kato R, Isaka K. Dienogest compared with gonadotropin-releasing hormone agonist after conservative surgery for endometriosis. J Obstet Gynaecol Res. 2016 Sep;42(9):1152-8. doi: 10.1111/jog.13023. Epub 2016 May 26. PMID: 27225336.
  4. Zakhari A, Edwards D, Ryu M, Matelski JJ, Bougie O, Murji A. Dienogest and the Risk of Endometriosis Recurrence Following Surgery: A Systematic Review and Meta-analysis. J Minim Invasive Gynecol. 2020 Nov-Dec;27(7):1503-1510. doi: 10.1016/j.jmig.2020.05.007. Epub 2020 May 16. PMID: 32428571.
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Dr. med. Nadine Rohloff