Menstrual and Uterine Disorders
Figure 3: Effects of Dienogest in Pain Reduction in Long-term Treatment*
10 20 30 40
0 Before
These results are somehow surprising and worrying and they appear at odds with the well-recognized benefits of these agents for the treatment of endometriosis.3,26
contraceptives (OCs) during use and a potential detrimental effect after discontinuation.25
An alternative explanation seems ** ** ** Three months *Modified by Petraglia, et al., 2011;22 Six months During treatment **p<0.001 versus before.
It shows a higher impact on breakthrough bleeding and a lower body weight increase than the contraceptive pill.17
Dienogest is a hybrid between progesterone and 19-nortestosterone derivatives. It is an orally active, syntethic 19-nortestosterone derivative that exhibits selective binding to the progesterone receptors. It does not have significant androgenic activity – about one-third of cyproterone. It does not have any mineralcorticoid or glucocorticoid activity. Dienogest 2 mg/day inhibits ovulation and produces hypo-estrogenic and hyperprogestational endocrine environment, yet it only moderately suppresses estradiol levels. Moreover, it has also shown inhibitory activity on various components of the inflammatory response, as well as inhibiting angiogenesis. Oral dienogest (2 mg/day for 12 weeks) was shown to be significantly better than placebo in reducing pelvic pain in patients with endometriosis in a double-blind trial, despite a substantial placebo response of approximately 21–26 % for VAS (visual analog scale) pain and improvement/satisfaction scores.18,19
In trials comparing oral dienogest
with GnRH agonists that are commonly used in the treatment of endometriosis, dienogest was equivalent to depot leuprolin in reducing pelvic pain and was not significantly different from depot triptorelin in improving symptoms. The improvements noted during treatment with oral dienogest (2 mg/day for 12–24 weeks) were sustained during long-term treatment for up to 65 weeks. In one study, the patients were shown to experience continued improvement between 24 and 52 weeks after the treatment discontinuation (see Figure 3).20,21
Dienogest appeared to have
fewer hypo-estrogenic adverse effects than GnRH agonists and in particular, did not produce significant reduction in bone mineral density. Dienogest was not considered to be associated with significant androgenic effects and was generally well tolerated. The efficacy and tolerability of dienogest were sustained during long-term therapy for more than one year and remained effective for six months after treatment interruption.22
Oestrogen-progestin Combination
There is a general consensus that oestroprogestins represent a valuable option for treating the disease.23
They establish a steady hormonal
environment that suppresses ectopic implants, reduces inflammation and prevents the formation of ovarian endometriomas by inhibiting ovulation. This action translates into an improvement of pain symptoms and prevention of recurrences in a consistent proportion of women.24 A recent meta-analysis of 18 studies, suggests a protective effect of oral
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OC treatment reduces the rate of post-operative endometrioma recurrence and should now be considered an essential part of long-term therapeutic strategies in order to limit further damage to future fertility.28 Their effect is limited to the period of use and endometriosis activity is reduced.29
Continuous administration without a seven day break, to avoid withdrawal bleeding, may be more beneficial in terms of pain relief.30 Therefore, preventing withdrawal bleeding may improve the efficacy of OCs for relief of pain associated with endometriosis.28–30
New Possible Treatments for Endometriosis Aromatase Inhibitors
The use of aromatase inhibitors for medical management of endometriosis is still experimental and is based on the observation that endometriotic lesions express the enzyme aromatase and are able to make their own estrogen, even in the absence of gonadotropin stimulation. The aromatase enzyme catalyses a terminal steroidogenesis step that leads to estrogen synthesis, by converting androgens into estrogens in a unidirectional pathway. The control of local estrogen production is modulated through the changes of aromatase. There are distinct tissue specific promoters of aromatase, each of which is regulated by different hormonal factors and second messenger signaling pathways.31
Sufficient circulating
levels of oestradiol, can be produced as a result of extraglandular aromatisation of androstenedione to estrone that is subsequently reduced to estradiol in peripheral tissues. The third generation of aromatase inhibitors effectively block oestrogen synthesis without affecting glucocorticoids, mineralcorticoids, or thyroxine secretion. They are currently available for clinical use as oral tablets and they are approved in postmenopausal women with breast cancer.32
Recent
studies examined pain relief after six months of daily treatment with an aromatase inhibitor together with high-dose norethindrone acetate or an OC and showed significant (but not complete) resolution of pelvic pain in women with endometriosis who had not responded to first-line treatment. Further research is required to determine if aromatase inhibitors will be safe and effective for long-term use in women with endometriosis pain.33,34
Aromatase inhibitors are also
believed to have the following roles in endometriosis-associated infertility: suppressing endometriotic lesions and ovarian stimulation agents.35,36
In general, third generation aromatase inhibitors have been found to be very well tolerated with few significant side effects and a low rate of discontinuation due to adverse reactions.
US OBSTETRICS & GYNECOLOGY 12 months
plausible, as the trend toward an increase in risk observed after previous oestroprogestin use may be due to confounders. Of relevance is that endometriosis is generally diagnosed several years after its development and that dysmenorrhea, a typical presenting symptom of the disease, is commonly treated with these agents. In other words, affected women may start assuming estroprogestins to treat endometriosis-related symptoms when they are yet not aware of being affected. It is also noteworthy that the mean time between symptoms’ appearance and diagnosis is estimated at seven to ten years.26,27 implants quiescent and improve pain symptoms.
Estroprogestins keep the
Visual analogue scale
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