The localisation of endometrial lesions vary. The most commonly affected sites include the ovaries, followed by the posterior broad ligament, the anterior cul-de-sac, the posterior cul-de-sac, and the uterosacral ligament. Endometriotic nodules can also affect the intestinal tract and the urinary system.³

Apart from chronic pelvic pain, other symptoms of endometriosis include: Dysmenorrhea, dyspareunia, dysuria, dyschezia, painful rectal bleeding, haematuria, shoulder tip pain, pneumothorax, cyclical cough, chest pain, haemoptysis, cyclical scar swelling, fatigue and impaired fertility (50%).⁵

Studies show that symptoms of endometriosis negatively impact patients’ quality of life (QoL). An international survey showed that patients living with endometriosis reported a substantial (38%) reduction in work productivity as a result of pain. Endometriosis also impacts mental health, with one study showing that 87% of patients living with endometriosis had depressive symptoms and 88% had anxiety. The severity of anxiety symptoms correlated with the intensity of pain.³

Risk factors for the development of endometriosis

Risk factors for the development of endometriosis include for example:^3,6

• Family history: Women who have a mother, sister, or daughter with endometriosis are more likely to develop the condition
• Early onset of menstruation: Women who start their periods at an early age (<11-years) may have a higher risk of developing endometriosis
• Menstrual cycle irregularities: Women who have shorter menstrual cycles (<27-days) or longer menstrual cycles (>28-days) may be at higher risk
• Never having been pregnant: Women who have never been pregnant may be at higher risk of endometriosis.

Diagnosis

According to the ESRHE guidelines, clinicians should consider a diagnosis of endometriosis in adult and adolescent patients presenting with the above-mentioned symptoms.¹

Although accuracy is low, the guidelines recommend a clinical examination, including a vaginal examination, to identify deep nodules or lesions in patients with suspected endometriosis. If the clinical examination is normal, but a diagnosis is suspected, additional tests should be conducted including imaging.¹

Classification ‘toolbox’

There is currently no gold standard for the classification of endometriosis and no single classification system adequately categorises the disease. The lack of consensus impacts decisions regarding optimal treatment, according to Lee et al.^7,8

In an attempt to address this issue, the World Endometriosis Society (WES) released a consensus statement on the classification of endometriosis in 2017. According to WES, healthcare practitioners should use a classification ‘toolbox’. They recommend:⁸

1. 1. 1. Patients undergoing surgery should have the Revised American Society for Reproductive Medicine or American Association of Gynecological Laparoscopists classification score and stage completed.
      2. Patients with deep endometriosis should have an Enzian classification completed.
      3. In patients for whom fertility is a future concern, the endometriosis fertility index score should be completed and documented in the medical/surgical records.

Managing symptoms

The most commonly prescribed treatments for endometriosis include drugs that alter the hormonal milieu, either by suppressing ovarian activity or by acting directly on steroid receptors and enzymes present in lesions.¹

These drugs include progestogens, anti-progestogens, combined oral contraceptives, gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists, levonorgestrel intrauterine devices, danazol (androgenic hormones), and aromatase inhibitors (AIs). AIs should be reserved for patients with pain refractory to other medical or surgical treatment, and should be prescribed in combination with oral contraceptives, progestogens, GnRH agonists or GnRH antagonists.¹

Combined contraceptives (oral, vaginal ring or transdermal) are recommended to manage endometriosis-associated dyspareunia, dysmenorrhoea and non-menstrual pain. In patients with dysmenorrhoea, continuous use of a combined contraceptive pill is recommended.¹ 

How does dienogest work?

Dienogest reduces lesions through a number of biological mechanisms. Dienogest is associated with relatively moderate inhibition of gonadotropin secretion, leading to a modest reduction in the endogenous production of oestradiol.⁹

When given continuously, dienogest induces a hypoestrogenic, hypergestagenic local endocrine environment, causing a decidualisation of endometrial tissue followed by atrophy of lesions.¹⁰

How safe and effective are dienogest?

According to Techatraisak et al, surgery is effective in alleviating endometriosis symptoms and improving QoL, however between 40% and 50% of patients have symptom recurrence, with 47% needing re-operation.¹¹

The long-term efficacy and safety of dienogest have been studied in numerous trials. Koninckx et al (2008) showed that treatment with dienogest reduced endometriosis-associated pain by 30% in patients with deep endometriosis, while Petraglia et al (2012) showed that treatment with dienogest significantly reduced pain by 83% over 65 weeks.^12,13

In a prospective open-label study by Ebert et al (2017) in adolescents (n=97) with clinically suspected or surgically confirmed endometriosis, the effect of dienogest on pain scores using the visual analogue scale (VAS), QoL, and lumbar spine bone mineral density (BMD) after one year were investigated.¹⁴

Mean VAS at baseline was 64.3mm. After 24 weeks of treatment, the mean VAS score was 9mm and 81% of participants experienced a reduction in VAS of ≥30%. Lumbar spine BMD decreased 1.2% after one year, but partially recovered after six months. The authors concluded that dienogest is as effective for endometriosis-associated pain in adolescents as in adults, but the need for tailored treatment in the adolescent population is important.¹⁴

Techatraisak et al (2022) conducted a prospective, non-interventional study in six Asian countries (n= 895). The primary endpoint was change in pain after six months of therapy with dienogest. The secondary objectives included change in scores at month six and 24, efficacy of dienogest in reducing endometriosis-associated pelvic pain, defined as pain at menstruation, chronic pelvic pain irrelevant to menstruation, and/or dyspareunia. Their results showed that 83.7% and 87.% of patients reported improvement of symptoms at months six and 24, respectively.¹¹

More recently, Gokmen et al (2023) assessed the effect of treatment with dienogest on the size of lesions and endometriosis-related pain symptoms over a six-month follow-up period.¹⁵

The mean size of lesions decreased significantly from an initial measurement of 44.0 ± 13mm to 39.5 ± 15mm at three months and to 34.4 ± 18mm at the six-month follow-up. The mean dysmenorrhea VAS scores before treatment, at the three-month follow-up, and at the six-month follow-up were 6.9 ± 2.6, 4.3 ± 2.8, and 3.8 ± 2.7, respectively.¹⁵

Dysmenorrhoea VAS scores decreased significantly over the first three months. Similarly, the VAS score for dyspareunia decreased at three and six months compared with the pre-treatment value.¹⁵

Conclusions

Endometriosis symptoms negatively impact patients’ QoL. Endometriosis-associated pain can lead to loss of productivity, depression and anxiety. Guidelines recommend progestogens as first-line therapy for the management of endometriosis-associated pain. Numerous studies have shown that dienogest 2mg is safe and effective for use in adolescent as well as adult patients.

References

1. Becker CM, Bokor A, Heikinheimo O, et al. ESHRE guideline: endometriosis. Human Reproduction Open, 2022.
2. Botha DJ, De Bruin A, Dryer S, et al. South African Guideline for Treatment of Endometriosis. Human Reproduction, 2014.
3. Tsamantioti ES, Mahdy H. Endometriosis. [Updated 2023 Jan 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.https://www.ncbi.nlm.nih.gov/books/NBK567777/#!po=75.9259
4. Schindler AE. Dienogest in long-term treatment of endometriosis. Int J Womens Health, 2011.
5. ESHRE. Information on Endometriosis. file:///C:/Users/rene.bosman/Downloads/ESHRE%20ENDOMETRIOSIS%20patient%20Guideline_21032022.pdf
6. Parasar P, Ozcan P, Terry KL. Endometriosis: Epidemiology, Diagnosis and Clinical Management. Curr Obstet Gynecol Rep, 2017.
7. Lee SY, Koo YJ, Lee DH. Classification of endometriosis. Yeungnam Univ J Med, 2021.
8. Johnson NP, Hummelshoj L, Adamson GD, et al. World Endometriosis Society consensus on the classification of endometriosis. Hum Reprod, 2017.
9. Sasagawa S, Shimizu Y, Kami H, et al. Dienogest is a selective progesterone receptor agonist in transactivation analysis with potent oral endometrial activity due to its efficient pharmacokinetic profile. Steroids, 2008.
10. Sasagawa S, Shimizu Y, Nagaoka T, et al. Dienogest, a selective progestin, reduces plasma estradiol level through induction of apoptosis of granulosa cells in the ovarian dominant follicle without follicle-stimulating hormone suppression in monkeys. J Endocrinol Invest, 2008.
11. Techatraisak K, Hestiantoro A, Soon R, et al. Impact of Long-Term Dienogest Therapy on Quality of Life in Asian Women with Endometriosis: the Prospective Non-Interventional Study ENVISIOeN. Reprod Sci, 2022.
12. Petraglia F, Hornung D, Seitz C, et al. Reduced pelvic pain in women with endometriosis: efficacy of long-term dienogest treatment. Arch Gynecol Obstet, 2012.
13. Koninckx PR, Craessaerts M, Timmerman D, Cornillie F, Kennedy S. Anti-TNF-alpha treatment for deep endometriosis-associated pain: a randomized placebo-controlled trial. Hum Reprod, 2008.
14. Ebert AD, Dong L, Merz M, Kirsch B, Francuski M, et al. Dienogest 2 mg Daily in the Treatment of Adolescents with Clinically Suspected Endometriosis: The VISanne Study to Assess Safety in ADOlescents. J Pediatr Adolesc Gynecol, 2017
15. Gokmen SB, Selcuki TNF, Aydın A, Bahat YP, Akça A. Effects of Dienogest Therapy on Endometriosis-Related Dysmenorrhea, Dyspareunia, and Endometrioma Size. Cureus, 2023.