Diffuse massive adenomyosis and infertility. Is it possible to treat this condition?

Background Severe forms of adenomyosis are a serious gynecological problem. In most cases, conservative treatment of this pathology is unsuccessful. Adenomyomectomy by Osada's approach seems to be the most promising solution. The present study evaluated the follow-up results of this type of surgery in patients with adenomyosis and infertility. Materials and methods The prospective study included 26 patients with severe forms of adenomyosis who underwent an adenomyomectomy using Osada's approach. In 18 patients (69%), infertility was the main indication for surgical treatment. The follow-up period lasted from July 2012 to January 2018. Results The median post-operative follow-up period was 18 months. For the first 12 months patients received hormonal therapy. In all postoperative patients, the menstrual cycle had normalized, and other symptoms of the disease had disappeared. Seven patients continue to receive postoperative hormonal treatment. Three individuals got spontaneously pregnant; two of them delivered full-term babies by cesarean section. Six patients are planning a pregnancy with assisted reproductive technology. Conclusion In the present study, the organ-preserving surgery of severe adenomyosis performed using Osada's method appeared to be a good alternative to hysterectomy. It stopped the development of pathological symptoms of the disease and restored the patient's reproductive function.

New data about preeclampsia: some possibilities of prevention.

This concise report deals with the known effects of progestogen lack in early pregnancy with failure of implantation and blood supply to the placenta depending on proper trophoblast invasion, spiral artery remodeling, and vessel dilatation. The pathophysiology of preeclampsia will be outlined and the most recent data on the effect of dydrogesterone presented. Dydrogesterone appears to be able to reduce significantly the development of preeclampsia. The effect is related to begin with such prevention and this should be continued until 37th weeks of gestation which would also mean prevention of premature labor.

Antiandrogenic and antimineralocorticoid health benefits of COC containing newer progestogens: dienogest and drospirenone.

Data have demonstrated that COCs, besides offering a satisfactory and safe contraception, offer a variety of non-contraceptive health benefits and therapeutic positive aspects. Many prescribes and users, however, do not realize these positive aspects especially the non-contraceptive health benefits. While the contraceptive use is the primary indication for COC use for most women, these users should be advised in regard of the non-contraceptive benefits when contraception is discussed and prescribed. Using COCs specifically for non-contraceptive indications is an off-label use in many clinical situations (only some exceptions as e.g. acne vulgaris in some countries are allowed clinical entities for the use of these drugs). Therefore, appropriate discussions with the patient regarding this fact should performed and documented by the prescribing physicians. Independent of the off-label situation, COCs containing the newer progestogens dienogest and drospirenone with their antiandrogenic and antimineralocorticoid health benefits play an important role in the management of many diseases and their use should therefore be considered by clinician's. This review will focus on the effects of these COCs on the endometrium, the skin, the fat tissue and the premenstrual syndrome.

The evolution of genomic stability to a mechanism in reproduction and psychiatry.

There are two forms of immune defense, the specific or adaptive immune defense and the unspecific innate immune defense. Vaccination is utilized against specific bacteria via the adaptive immune system. The innate immunity DNA stress defense is a non-toxic mechanism developed in yeasts and conserved in mammals and in plants. Although the steroidal hormone cascade has overtaken the stress response and allows superfast response via non-genomic receptors, the old innate immunity response is still mediated via the steroidal hormones cascade. The classical drug/receptor model has provided for many solutions, however, in antibiotics, cancer, and in severe mental diseases this model reaches to certain limits. The NIH/Department of Mental Health has developed a new model that shows severe mental diseases may be immune diseases that can be treated by replacing old diseased nerve cells by new healthy nerve cells, where the old innate immunity may be exploited. This means that severe mental diseases are physical diseases. A newly developed model, where modifications of the steroidal hormone cascade help to understand bipolarity, schizophrenia, and PTSD in men and women can be transferred to gynecological hormone modifications in women, where innate immunity is mediated via the same steroidal hormone cascade. Treatment via immune response via the DNA cascade should be developed in cancer, infections and severe mental disease, because foreign cells or diseased cells may be removed by the unspecific innate immunity.

Present and future aspects of dydrogesterone in prevention or treatment of pregnancy disorders: an outlook.

Over time, it became evident that with the use of micronized progesterone and dydrogesterone prevention or treatment of pregnancy disorders such as threatened miscarriage, recurrent (habitual) miscarriage, preterm labor or preeclampsia appears to be possible. The results so far obtained will be delineated and concepts of prevention or treatment are suggested with the aim to further explore these pregnancy disorders either by prevention or treatment concepts to obtain not only benefits to the mother and the fetus, but furthermore this results in benefits for lifetime for the individual, for the family and last but not least for society.

Successful prevention of preeclampsia in a high-risk pregnancy using progestogen dydrogesterone: a clinical case.

The presented clinical example convincingly demonstrates the efficacy of dydrogesterone (30 mg) in the prevention of severe preeclampsia in a high-risk patient (early development of preeclampsia and preterm Cesarean section in her first pregnancy, arterial hypertension). This case suggests using dydrogesterone as an option to prevent preeclampsia, as previously shown in a prospective randomized study.

Review on role of progestogen (dydrogesterone) in the prevention of gestational hypertension.

INTRODUCTION: Gestational hypertension remains one of the main causes of maternal deaths all over the world. Attempts to reduce/prevent the incidence had failed due to lack of understanding of the disease's aetiology. One of the early roles of natural progesterone in the first trimester of pregnancy is to promote formation of wide-calibre spiral vessels that invade into the myometrial layer of the gravid uterus. Theoretically, this will prevent or reduce the incidence of gestational hypertension in the latter half of the pregnancy. REVIEW: The progestogen, dydrogesterone, has similar molecular structure and properties to natural progesterone. A pilot study was undertaken on primigravidae, who have higher risk of developing gestational hypertension. They were supplemented with dydrogesterone in the first trimester (Study Group) and compared with a similar number of primigravidae (Control Group) without supplementation with the progestogen. The incidence of gestational hypertension was significantly lower in the Study Group as compared to the Control Group (1.7% vs. 12.9%, respectively, p<0.001). The incidence of foetal distress was also significantly lower in the Study Group compared to the Control Group (4.3% vs. 18.1%, respectively, p<0.001). CONCLUSION: Supplementation of the progestogen, dydrogesterone, in the first trimester to primigravidae has shown great potential in reducing or preventing the incidence of gestational hypertension.

Drospirenone as estrogen-free pill and hemostasis: coagulatory study results comparing a novel 4 mg formulation in a 24 + 4 cycle with desogestrel 75 µg per day.

INTRODUCTION: A novel estrogen free contraceptive pill, with drospirenone 4 mg in a dosing regimen of 24 + 4, has been developed with a pearl-index of 0.51 (95% CI 0.1054; 1.4922). The aim of the following study was to determine if 4 mg DRSP has an impact on coagulation factors and thrombotic risks in comparison with desogestrel 75 µg. PATIENTS AND METHODS: Thirty-nine patients received 4 mg DRSP 24 + 4 d and 29 desogestrel 75 µg per day continuously during nine complete cycles. Following hemostatic parameters were evaluated: Apc resistance, Antithrombin III, Protein C reactivity, Factor VII, Factor VIII, and d-Dimer. RESULTS: Factor VII decreased from 1.123 to 1.066 in the DRSP group and from 1.241 to 1.034 in the desogestrel group (p = 0.0088). The difference in change of mean Protein C activity from baseline to endpoint was -0.0332 in the DRSP versus -0.157 in the desogestrel group (p = 0.0249). d-Dimer values dropped in the DRSP group from baseline values of 264.9-215.0 ng/mL, whereas in the desogestrel group there was a rise from 201.4 ng/mL to 281.5 ng/mL. DISCUSSION: DRSP 4 mg was not associated with any meaningful changes on hemostatic parameters, indicating a lack of effect on hemostasis.

Dydrogesterone and pre-term birth.

Progestin supplementation appears to be a promising approach to both preventing initiation of pre-term labor and treating it once it is already established. Successful pregnancy depends on maternal tolerance of the fetal "semi-allograft". A protein called progesterone-induced blocking factor (PIBF), by inducing a Th2 dominant cytokine production mediates the immunological effects of progesterone. Over time, various attempts have been made to clarify the question, whether progestogens can contribute positively to either prevention or treatment of pre-term labor and birth. Dydrogesterone treatment of women at risk of pre-term delivery results in increased PIBF production and IL-10 concentrations, and lower concentrations of IFNγ and could be effective for prevention or treatment of pre-term labor. Further randomized studies are needed.

European Progestin Club Guidelines for prevention and treatment of threatened or recurrent (habitual) miscarriage with progestogens.

This guideline has been developed based on studied and clinical investigations. Therefore, it appears to be appropriate to use all the available evidence, which are very encouraging, in a summarized form to propose guidelines by a group of European experts in order to give the gynecologists, obstetricians and reproductive medicine specialists have direction with regard to the prevention or treatment of miscarriage for the benefit of the endangered pregnancies. There are a number of statements, opinions and guidelines already published for this topic, which are not entirely in agreement.

Comparison of steady state development and reduction of menopausal symptoms after oral or transdermal delivery of 17-ß-estradiol in young healthy symptomatic menopausal women.

OBJECTIVE: There is a renewed interest in the delivery of estradiol (E2) for the reduction of menopausal symptoms in young symptomatic menopausal women. This paper compares experimentally and theoretically obtained E2 plasma values by oral and transdermal delivery and compares them with relevant menopausal symptoms. STUDY DESIGN: Two independent previously published studies were compared, which each contained 42 young symptomatic menopausal women. Experimentally obtained plasma values at days 1, 7 and 21 were compared with a theoretical model, taken from the literature, for describing plasma values for an oral immediate release formulation, consecutively for 21 days. Menopausal symptoms were determined in the steady state for oral and transdermal delivery with the Kuppermann index, previously not reported. In the case of oral delivery, estradiol was compared with estradiol valerate. RESULTS: Previously published results for transdermal delivery of E2 showed that the matrix system establishes a steady state condition with the application of the first patch. Excellent agreement between theoretically predicted and experimentally obtained E2 plasma values for oral delivery in menopausal women was obtained. Circadian E2 plasma levels were observed continuously for transdermal delivery, were seen in oral delivery during first application and disappeared when steady state was achieved. Application of the prodrug E2-valerate delayed the maximum plasma peak from 1 pm to 4 pm, similar to the transdermal matrix patch. Investigating menopausal symptoms determined with the Kuppermann index did not reveal differences between oral or transdermal "E2 kinetic (hot flushes) relationship". This relationship was similar to symptomatic women suffering from hot flushes in untreated menopausal women or premenopausal women. Different menopausal symptoms required different E2 plasma levels: the average E2 levels higher than 23 pg/mL in plasma did abolish insomnia in 50% of postmenopausal women, with 28 pg/mL is needed to suppress 50% of dysthymia; however, rather high levels of 41 pg/mL are needed to suppress 50% of hot flushes, suggesting a rather complex mechanism beyond an E2 receptor mediated process. CONCLUSION: There is a difference in the steady state between oral and transdermal E2 delivery. Steady state condition is achieved in the first application of a matrix patch, whereas with the application of a tablet the steady state is achieved in transdermal delivery within 12-14 days. Our reported calculated missed intake of a E2 tablet shows that E2 plasma levels drop for 4 days consecutively. Our conducted study has several limitations: firstly, no cross-over was conducted, but a rather cumbersome mathematical modeling; secondly, healthy women with no accompanying severe diseases were included in this study. The higher the oral dose, the higher the E2 steady state levels, but the time to achieve steady state levels is independent from the E2 dose.

Nomegestrol acetate/estradiol hormonal oral contraceptive and breast cancer risk.

Combined hormonal contraceptives (CHCs) contain estrogen and progestin, which can stimulate estrogen-sensitive and/or progesterone-sensitive breast cancer growth. Until recently, ethinylestradiol had been almost the only estrogen used for decades, and its dose has been greatly reduced over time. The first generations of birth control pills contained approximately five times more estrogen and four times more progestin than the latest contraceptives. Newer CHCs also contain steroids that more closely mimic the physiological estradiol (E2) and progesterone effects. The newer CHC formulations are thus expected to have less influence on the breast, although it is very difficult to demonstrate any difference among the recent available preparations in human studies. Recently, nomegestrol acetate (NOMAC), a neutral, nonandrogenic, progesterone-like profile progestin, has become available in combination with the 'natural' estrogen, E2. According to the literature, NOMAC/E2 is expected to have either a lesser stimulating effect or a neutral effect on estrogen-sensitive breast cancers. We performed an analysis of the available studies and a bibliographical review. The endocrine and metabolic effects of NOMAC/E2 formulation might lead to a lesser breast tissue stimulation. The data reported, confirmed through clinical studies, should be considered when choosing a hormonal contraceptive, especially when breast stimulation is a concern.

The "newer" progestogens and postmenopausal hormone therapy (HRT).

After a worldwide breakdown of hormone therapy [HT] following the publications of the Women's Health Initiative trial and Million Women's Study in 2002-2003, there is now a trend to turn attention again to HT and to explore particular progestogens, which have been discredited with respect to their side effects. The progestogens to be considered should control undue proliferation of the endometrium and should not interfere negatively with the positive effects of estradiol, regarding carbohydrate and lipid metabolism as well as hemostasis. In the present review, three "newer progestogens" are scrutinized regarding their various actions, in combination with estradiol; the progestogens include dienogest, drospirenone and nomegestrol acetate. This article is part of a special issue entitled Menopause.

Non-contraceptive benefits of oral hormonal contraceptives.

It is becoming evident that oral hormonal contraceptives-besides being well established contraceptives-seem to become important medications for many functional or organic disturbances. So far, clinical effectiveness has been shown for treatment as well as prevention of menstrual bleeding disorders and menstrual-related pain symptoms. Also this is true for premenstrual syndrome (PMS) and premenstrual disphoric disorder (PMDD). Particular oral contraceptives (OCs) containing anti-androgenic progestogens were shown to be effective medications for treatment of androgenisation symptoms (seborrhea, acne, hirsutism, alopecia). Through perfect suppression of the hypothalamic-pituitary-ovarian axis OCs have proven to be effective in elimination of persistent follicular cysts. Endometriosis/adenomyosis related pain symptoms are well handled similar to other drugs like Gonadotropine Releasing Hormone agonists but are less expensive, with less side effects, and possibility to be used for longer periods of time. This is also true for myoma. Pelvic inflammatory disease, rheumatoid arthritis, menstrual migraine, and onset of multiple sclerosis are prevented or delayed. Bone density is preserved and asthma symptoms improved. Endometrial hyperplasia and benign breast disease can be controlled. There is definitely a significant impact on risk reduction regarding endometrial, ovarian, and colon cancers. In conclusion, it needs to be recognized that oral combined hormonal contraceptives (estrogen/ progestogen combination) are - besides being reliable forms of contraception - are cost-effective medications for many medical disorders in women. Therefore, these contraceptives drugs are important for female and global health and should be used in clinical practice.

Balancing steroidal hormone cascade in treatment-resistant veteran soldiers with PTSD using a fermented soy product (FSWW08): a pilot study.

UNLABELLED: Abstract Introduction: A clinical study was conducted to determine steroidal hormone cascade in the blood to relate them to mental performance with the Clinician-Administered PTSD scale (CAPS), serum lipid concentrations, and steroidal hormones, particularly cortisol, testosterone, estradiol, dehydroepiandrosterone (DHEA), and pregnenolone, in treatment-resistant male veterans with combat-related chronic posttraumatic stress disorder (PTSD) before and after consumption of a special fermented soy formulation (FSWW08). Admitted veterans in the study were resistant to conventional psychological and pharmacological therapies. METHOD: Ten treatment-resistant soldiers with combat-related PTSD (according to the International Classification of Diseases, 10th Revision code) for ≤1.5 years were enrolled in this study. A specially formulated fermented soy product, FSWW08, was given to the veterans for 3 months and then extended to 6 months. CAPS was used to assess the severity of PTSD. Immunologic cytokines, triglycerides, and 16 steroidal hormones were also determined from the blood of the PTSD patients before, during, and after consumption of the FSWW08. RESULTS: FSWW08 increased blood levels of steroids, such as testosterone, estradiol, and particularly the adrenal hormones cortisol and androstenediol. Decreased steroidal hormones from the upper part of the hormone cascade, such as cholesterol, DHEA, and pregnenolone were experienced. The arteriosclerotic risk was reduced (cholesterol, 280±35 to 205±22 mmol/L, p<0.001; triglycerides, 645±267 to 161±22 mg/dL, p<0.001; very-low-density lipoprotein cholesterol, 312±112 to 151±20 mg/dL, p<0.001; homocysteine in serum (i.s.), 26±4 to 11.8±2.1 µmol/L, p<0.001). High-density lipoprotein cholesterol concentration was significantly lower after consumption of FSWW08 (51±15 to 89±7.8 mg/dL, p<0.001). FSWW08 significantly reduced mental symptoms according to CAPS after 7 days throughout the 6-month study. Insomnia (estradiol increased from 53±24 to 88±41 pg/L), breathing disorders (may be related to increased aldosterone) are hormone dependent and were corrected in those with insomnia. The increase in testosterone and decrease in prolactin was corroborated by an increase in sex drive and improved partner relationships. Common immunity disorders of the veterans, such as increased herpes labialis, flu-like syndromes, and stomach pain were resolved in all veterans and was corroborated by significant improvements in immunologic cytokines: tumor necrosis factor α was reduced (from 13.5±0.4 to 9.0±1.4 pg/mL, p<0.001) and interleukin ß (from 7.0±0.5 to 4.5±1.8 pg/mL) and interferon γ (from 10.4±2.4 to 6.3±1.5 pg/mL, p=0.001) were also detected. PTSD is associated with clinically elevated leukocytes and lymphocytes, which are reduced by FSWW08 as well. CONCLUSION: It is the first time that the normalization of the whole steroidal hormone cascade in the blood could be correlated with improvements in mental and physical parameters (especially metabolic and immunologic disorders) in veterans with combat-related and treatment-resistant PTSD. Studies of FSWW08 in larger cohorts and over longer periods of time, as well as dosing effects, have to be conducted to validate these results.

Dienogest in long-term treatment of endometriosis.

Endometriosis is a chronic disease primarily affecting women of childbearing age, in which endometriotic lesions form outside the uterus, typically leading to painful symptoms, fatigue, and infertility. The symptoms of endometriosis may cause significant impairment in quality of life and represent a substantial economic burden to patients, families, and society. There is no cure for endometriosis; management consists of alleviating pain and other symptoms, reducing endometriotic lesions, and improving quality of life. Recurrence after surgical intervention is common, while the clinical evidence to support the efficacy and safety of many medications currently used in endometriosis is limited. Dienogest is an oral progestin that has been investigated extensively in the treatment of endometriosis in two clinical programs performed in Europe and Japan, including dose-ranging, placebo-controlled, active comparator-controlled, and long-term (up to 65 weeks) studies. These studies demonstrated that dienogest 2 mg daily effectively alleviates the painful symptoms of endometriosis, reduces endometriotic lesions, and improves indices of quality of life. Dienogest showed a favorable safety and tolerability profile in these studies, with predictable adverse effects, high rates of patient compliance, and low withdrawal rates. This review article describes the clinical trial evidence that characterizes the efficacy and safety of dienogest in endometriosis, including two studies characterizing dienogest in long-term use. The relevance of these findings to the management of endometriosis in clinical practice is discussed.