Novel triple therapy for hemorrhagic ascites caused by endometriosis: A case report

BACKGROUNDMassive hemorrhagic ascites caused by endometriosis is exceedingly rare, and the treatment strategy remains controversial. Here, we report a case of endometriosis with massive hemorrhagic ascites treated with a novel triple therapy including conservative surgery, gonadotropin-releasing hormone agonist, and then dienogest.CASE SUMMARYA 28-year-old nulliparous patient was admitted to Shengjing Hospital of China Medical University, and exploratory laparoscopy was performed. A total of 9500 mL of brown ascites was aspirated from the pelvic cavity, the bilateral ovaries strongly adhered to the posterior of the uterus and were fixed to the pelvic floor, and endometriotic cysts were not observed in either ovary. The pelvic and abdominal peritonea were covered with patchy red, white, and brown endometriotic lesions and defects. Partial surgical resection of endometriotic lesions on the peritoneum was performed while we simultaneously collected multiple peritoneal biopsies. The final pathological diagnosis was endometriosis coupled with hemorrhagic necrotic tissue.CONCLUSIONPostoperative injection of gonadotropin-releasing hormone agonist was provided three times, followed by dienogest administration, and we will continue to follow up with this ongoing treatment.     

Effect of four different oral contraceptives on various sex hormones and serum-binding globulins

In a double-blind, controlled, randomized, four-arm, bicentric clinical study, the effect of four oral contraceptives (OCs) on various hormone parameters and serum-binding globulins was investigated. Four groups with 25 volunteers each (18-35 years of age) were treated for six cycles with monophasic combinations containing 21 tablets with either 30 microg ethinylestradiol (EE) + 2 mg dienogest (DNG) (30EE/DNG), 20 microg EE + 2 mg DNG (20EE/DNG), 10 microg EE + 2 mg estradiol valerate (EV) + 2 mg DNG (EE/EV/DNG) or 20 microg EE + 100 microg levonorgestrel (LNG) (EE/LNG). The study was completed by 91 subjects. Blood samples were taken after at least 12 h of fasting on Day 21-26 of the preceding control cycle and on Day 18-21 of the first, third and sixth treatment cycle. The serum concentrations of free testosterone were significantly decreased by about 40-60% in all four groups, while those of dehydroepiandrosterone sulfate (DHEAS) showed a time-dependent decrease during treatment. Except for EE/EV/DNG, which increased prolactin significantly during the third and sixth cycles, no change was observed with the EE-containing preparations. There was a significant increase in the levels of serum-binding globulins during treatment, which differed according to the composition of the OCs used. The rise in sex hormone-binding globulin (SHBG) was highest during intake of 30EE/DNG (+320%) and lowest with EE/LNG (+80%), while the effect of 20EE/DNG and EE/EV/DNG was similar (+270%). The thyroxine-binding globulin (TBG) levels increased significantly, by 50-60%, during treatment with the DNG-containing formulations, while the effect of EE/LNG was less significant (+30%). The rise in corticosteroid-binding globulin (CBG), which occurred in all groups, was most pronounced in women treated with 30EE/DNG (+90%) and least with EE/EV/DNG (+55%), indicating a strong influence of EE and no effect of the progestogen component. In all treatment groups, the frequency of intracyclic bleeding rose in the first treatment cycle and decreased thereafter. Cycle control was significantly better with 30EE/DNG or EE/LNG than with 20EE/DNG or EE/EV/DNG. There was no significant change in blood pressure, body mass index or pulse rate throughout the study. In conclusion, the DNG-containing OCs caused a higher rise in SHBG and TBG levels than the LNG-containing preparation. The effects on CBG suggest a lesser hepatic effect of 2 mg EV as compared to 20 or 30 microg EE. In contrast to EE, the use of estradiol in OCs appeared to increase prolactin release, while the cycle control was better with the OC containing 30 microg EE.     

Effect of four oral contraceptives on thyroid hormones,adrenal and blood pressure parameters

In a double-blind, controlled, randomized, four-arm, bicentric clinical study, the effect of four oral contraceptives (OCs) on thyroid hormone parameters, cortisol, aldosterone, endothelin-1 and angiotensin II was investigated. Four groups composed of 25 volunteers each (ages between 18 and 35 years) were treated for six cycles with monophasic combinations containing 21 tablets with either 30 microg ethinylestradiol (EE) + 2 mg dienogest (DNG) (30EE/DNG), 20 microg EE + 2 mg DNG (20EE/DNG), 10 microg EE + 2 mg estradiol valerate (EV) + 2 mg DNG (EE/EV/DNG) or 20 microg EE + 100 microg levonorgestrel (LNG) (EE/LNG). The study was completed by 91 subjects. Blood samples were taken by venipuncture after at least 12 h fasting on Day 21-26 of the control cycle and on Day 18-21 of the first, third and sixth treatment cycle. There was a significant increase in triiodothyronine (T3) and thyroxine (T4) by 20-40% in all treatment cycles, while thyroid-stimulating hormone was significantly increased only with EE/EV/DNG. Treatment with the DNG-containing OCs caused no change in free T4 (FT4) and a transitory reduction in free T3 (FT3) levels during the first cycle. During intake of EE/LNG, FT4 rose slightly, while FT3 was not altered. The pronounced rise in the serum concentrations of cortisol appeared to be related to the EE dose. During the first three cycles of treatment, no effect on angiotensin II levels was observed, while in the sixth cycle a significant decrease was measured in all treatment groups. The four OCs did not influence the serum concentrations of endothelin-1 and no consistent effects were found concerning those of aldosterone. The results suggest that the three DNG-containing and the LNG-containing low-dose OCs may increase T3, T4 and cortisol due to an elevated binding to serum globulins, while the free proportion of the hormones is not or only slightly changed. Therefore, these OCs have only minor effects on thyroid function, adrenal and blood pressure serum parameters.     

Bleeding pattern and cycle control with an estradiol-based oral contraceptive: a seven-cycle, randomized comparative trial of estradiol valerate/dienogest and ethinyl estradiol/levonorgestrel

Background

This study compared the bleeding pattern, cycle control and safety of an oral contraceptive (OC) comprising estradiol valerate/dienogest (E2V/DNG; administered using a dynamic dosing regimen) with a monophasic OC containing ethinyl estradiol 20 mcg/levonorgestrel 100 mcg (EE/LNG). E2V releases estradiol (E2), which is identical to endogenously produced 17β-estradiol.

Study design

This was a randomized, multicenter, double-blind, double-dummy trial lasting seven cycles in healthy women aged 18-50 years.

Results

Overall, 798 women were randomized and received allocated treatment (399 per group). There were significantly fewer bleeding/spotting days reported by women who received E2V/DNG than those who received EE/LNG [17.3±10.4 vs. 21.5±8.6, respectively, p<.0001, Reference Period 1 (Days 1-90); and 13.4±9.vs. 15.9±7.1, respectively, p<.0001, Reference Period 2 (Days 91-180)]. Through Cycles 1-7, the occurrence of scheduled withdrawal bleeding per cycle was 77.7-83.2% with E2V/DNG and 89.5-93.8% with EE/LNG (p<.0001 per cycle). The duration and intensity of scheduled withdrawal bleeding were reduced with E2V/DNG vs. EE/LNG. The incidence of intracyclic bleeding was similar with E2V/DNG (10.5%-18.6%) and EE/LNG (9.9%-17.1%) (p>.05 per cycle). No unintended pregnancies occurred with E2V/DNG, but there was one unintended pregnancy with EE/LNG. Adverse drug reactions occurred in 10.0% and 8.5% of women taking E2V/DNG and EE/LNG, respectively. Overall, 79.4% of women were satisfied with E2V/DNG and 79.9% with EE/LNG.

Conclusions

A novel OC composed of E2V/DNG is associated with an acceptable bleeding profile that is comparable to that of an EE-containing OC.     

The pharmacology of dienogest

Dienogest (DNG) is a 19-nortestosterone derivative (a C-19 progestogen) with a cyanomethyl instead of an ethinyl group at the C-17 position, which may make the compound elicit fewer hepatic effects than other C-19 nortestosterone derivatives. Its similarity to norethisterone is reflected in its high endometrial efficacy, which could explain the high stability of the menstrual cycle women achieve when they use DNG in combination with ethinyl estradiol (EE) or with estradiol valerate (E2V). Its strong endometrial efficacy underlies the use of DNG (on its own) to treat endometriosis, and gives it antiproliferative and anti-inflammatory effects in the treatment of endometriotic lesions. Properties derived from its C-19 derivative structure include its short plasma half-life, of about 10h (which means the drug is not accumulated), and its high oral bioavailability, of more than 90%. However, DNG also has some of the properties of typical of progesterone derivatives, including a lack of effect on the metabolic and cardiovascular systems, and considerable antiandrogenic activity, the latter increased by its lack of affinity to the sex-hormone binding globulin (SHBG), in contrast to other C-19 progestogens. DNG has no glucocorticoid and no antimineralocorticoid activity. It also has no antiestrogenic activity, which suggests that it should not antagonize estradiol's beneficial effects. This is important for its use in the treatment of endometriosis, because, due to DNG's low gonadotropic activity, E2 levels are not decreased to zero, in contrast to treatments with gonadotropin-releasing hormone (GnRH) analogues. This maintenance beneficial E2 effects is of particular importance for the general tolerability of the first contraceptive pill to use E2V instead of EE, although clinical endpoint studies are still ongoing. These studies are expected, on the basis of its pharmacology, to demonstrate the cardiovascular safety of the new pill.     

地诺孕素治疗对醋酸炔诺酮治疗效果不佳的子宫内膜异位症患者的疗效分析

目的:对于经常性疼痛和经醋酸炔诺酮治疗6个月后效果不佳的子宫内膜异位症患者,再经地诺孕素治疗6个月后患者的治疗效果满意度评价。方法:纳入65名患者进行两年的前瞻性研究;患者在经地诺孕素治疗期间与醋酸炔诺酮治疗期间效果的比较,主要观测指标采用李克特量表(Likert scale)进行测定,次要观测指标评价疼痛度、生活质量、性功能变化和囊肿体积的变化。结果:地诺孕素治疗3个月和6个月与醋酸炔诺酮治疗时基线值相比患者的满意度明显改善(P<0.001);EHP-30和FSFI对生活质量和性生活质量的评价表明,患者在治疗6个月后明显改善;在治疗期间子宫内膜异位的结节体积未发生明显变化。结论:本研究结果表明地诺孕素可以用于子宫内膜异位症患者有效的治疗手段,尤其是对于经醋酸炔诺酮治疗效果不佳的患者。对于地诺孕素和醋酸炔诺酮作为一线和二线治疗药物尚需进一步的临床对比性实验研究。     

Effect of dienogest on serum anti-Mullerian hormone level after laparoscopic cystectomy of ovarian endometrioma

ObjectiveThis comparative study aimed to evaluate the effect of postoperative dienogest treatment on serum anti-Mullerian hormone (AMH) levels in patients undergoing laparoscopic cystectomy of ovarian endometriomas.Materials and methodsA total of 71 patients with ovarian endometriomas treated at our department were enrolled. After surgery, 54 patients received oral dienogest 2 mg daily continuously for 6 months (dienogest group). The other 17 patients did not receive postoperative medical treatment (control group). Serum AMH levels were measured before surgery, at 3-month period after surgery, and at the end of 6-month follow-up period. Serial changes of AMH levels were compared between the two groups.ResultsThe age, endometrioma size, and serum AMH level before surgery were comparable between the dienogest group and the control group. The AMH levels decreased significantly at 3-month period after surgery in the dienogest group (a decrease of 65.5%; p < 0.001) and the control group (a decrease of 64.8%; p = 0.018). The AMH levels increased gradually from the nadir at 3-month period after surgery and recovered partially at the end of 6-month follow-up period in both groups. There were no statistically significant differences in the rate of reduction of serum AMH levels between the two groups (p = 0.707).ConclusionLaparoscopic cystectomy of ovarian endometrioma causes a significant decrease in serum AMH levels. The rates of reduction of AMH levels are similar regardless of dienogest treatment. Postoperative dienogest treatment for 6 months has no rescue effect on serum AMH levels in these patients.     

The efficacy and tolerability of Valette®: a postmarketing surveillance study

Objectives and methods A postmarketing survey was carried out to determine the efficacy and tolerability of Valette® (dienogest 2.0 mg and ethinylestradiol 0.03 mg) in routine gynecological practice.

Results Valette had excellent contraceptive efficacy (unadjusted Pearl index 0.14), with 11 unplanned pregnancies from a total of 92 146 cycles of exposure, of which at least four were attributable to user failure.

Cycle control was good, with spotting and breakthrough bleeding, which affected 5.0% and 3.4% of women, respectively, during the first cycle, becoming less frequent thereafter. Silent menstruation, i.e. the absence of withdrawal bleeding, affected on average 2.0% of women per cycle and 5.9% within the observation period.

Valette was well tolerated. The most common adverse drug reactions were mastalgia (1.46% of all users), weight gain (1.11%), headache (0.98%), nausea/vomiting (0.96%), dysmenorrhea (0.35%), decreased libido (0.31%) and depressive moods (0.28%). The dropout rate due to adverse drug reactions was only 3.2%. Only six of the 16267 women reported events which were considered to be serious adverse drug reactions; all recovered with appropriate treatment.

Conclusions These results confirm those from previous clinical trials, and demonstrate that Valette is highly effective, very well tolerated and produces excellent cycle control in routine practice.