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.

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.

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.

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.

Benefits and risks of ovarian function and reproduction for cancer development and prevention.

Ovarian function and menstrual cycle disturbances, pregnancy, and reproductive medicine procedures can either increase gynecological cancer risk or prevent cancer development. For ovarian cancer development, there are two hypotheses, which are connected with ovulation and gonadotropin secretion. Most of the ovarian cancers seem to be derived from displaced ovarian surfice epithelial cells. One year of ovulatory cycles increases the ovarian cancer risk by 6%. Ovulation between 22 and 29 years of age causes the highest risk increase per year. In contrast, progesterone or progestins appear to create protection. Lifestyle can affect or modify ovarian cancer risk. Breast cancer risk is very much related to age of menarche and menopause, pregnancy, and breast feeding. All of which are related to ovarian function and progestogenic impact that translates either into breast cancer risk increase or decrease. This is modified by body mass index, physical activity, and lifestyle in general. The risk of endometrial cancer is most closely related to endogenous progesterone during the menstrual cycle and pregnancy or by exogenous progestogens as in oral contraceptives. These effects are progestogen dose and time dependent. Endometrial cancer risk can also be increased by estrogen-producing tumors or long-term estrogen treatment.

Dydrogesterone and other progestins in benign breast disease: an overview.

Progestogens appear to have a dual effect on the cell cycle in breast cells and breast cancer cells. There is initially stimulation of mitotic activity. However, continuous application leads to cell apoptosis. This depends on type, dose and length of progestogen application in relation to estrogen action. In benign breast disease the use of progestogens results not only in reduction of mastodynia, but also a reduction in breast gland size and disappearance of nodularity proven by clinical examination and follow-up including breast ultrasound.

Hormonal contraceptives and endometriosis/adenomyosis.

Over the past 50 years hormonal contraceptives have gradually developed to be cost-effective medical treatment modalities for primary and secondary therapy of endometriosis/adenomyosis. This is particularly true for the various estrogen/progestogen combinations as monophasic - particularly progestogen-dominant - preparations in cyclic, long-cyclic and continuous treatment forms. An alternative is the progestogen-only therapy used continuously. Therapeutic effects have been shown for peritoneal, ovarian and deep-infiltrating endometriosis as well as for adenomyosis. An individualized, medical long-term treatment concept to control endometriosis/adenomyosis-related symptoms, endometriosis/adenomyosis development and minimizing the recurrence rate needs to be further studied in women, who do not desire to become pregnant.

Effect and safety of high-dose dienogest (20 mg/day) in the treatment of women with endometriosis.

PURPOSE: Hormonal treatment of endometriosis is often continued for long periods and has the potential to affect many essential metabolic processes. The current study aimed to determine the effects and safety of high-dose dienogest as a medical endometriosis therapy. METHODS: The effects and safety of high-dose dienogest, 20-30 mg/day for 24 weeks, were examined in 21 women aged 18-52 years with laparoscopically and histologically proven endometriosis stage I-IV (according to revised American Society of Reproductive Medicine criteria). At baseline and week 24, sera were obtained and stored at -20°C prior to analysis. RESULTS: The study showed no clinically significant effect of high-dose dienogest on thyroid or adrenal function, electrolyte balance or haematopoiesis. High-dose dienogest therapy also had no appreciable effects on glucose and lipid metabolism, liver enzymes or haemostasis. For instance, although dienogest mediated small increases in the haemostatic variables prothrombin fragment 1 + 2, antithrombin III and protein C, final levels (at week 24) remained within normal reference ranges for these parameters. The exception was the HDL-3 cholesterol concentration at week 24 (0.97 mmol/l), which increased beyond the normal range of 0.28-0.64 mmol/l. CONCLUSIONS: This investigation yielded a unique dataset on the safety of high-dose dienogest in endometriosis stage I-IV. High-dose dienogest (20-30 mg/day) had little influence upon all the parameters measured. It is therefore likely that lower doses of dienogest would have similarly neutral safety effects: an important consideration in the use of dienogest for the treatment of endometriosis.

Dienogest and the breast.

In a clinical pilot study, 21 women with endometriosis have been primarely treated with dienogest 2 x 10 mg daily p.o. for 24 weeks. Besides the effect on endometriosis the action of such high-dose progestogen treatment on the breast was evaluated by breast ultrasound prior to medication and at 24 weeks of medical treatment. In all women, a significant size reduction of the mammary gland (p < 0.023) and regression of mastopathic changes were observed. There was a non-significant reduction (p = 0.089) of the maximum diameter of the ducts. The portion of the fatty tissue increased slightly, but not significantly (p = 0.348).

Genotyping of a Chinese family with 46,XX and 46,XY 17-hydroxylase deficiency.

BACKGROUND: 17-Hydroxylase deficiency is a rare form of congenital adrenal hyperplasia caused by CYP17A1 gene mutations. METHOD: A 46,XY and a 46,XX Chinese patients with 17-hydroxylase deficiency in a family and their four generations family members were genotyped by PCR-sequencing method. RESULTS: Two CYP17 gene mutations were identified from these patients. Among them, IVS1-1G > A was a novel splicing mutation which disrupted the acceptor signal of exon 2 and might create a new exon after exon 1. The indel mutation of TAC329AA was a one-base deletion mutation and one-base change at codon 329 in exon 6. CONCLUSION: The results confirmed the diagnosis of 17-hydroxylase deficiency in these two patients and their autosome recessive heritage mode. The TAC329AA indel mutation had been identified in several reports of Chinese and Asian, suggesting that codon 329 was an unstable point of the CYP17 gene and this mutation was a prevalent CYP17 mutation in the Asian population. Although the noval mutation IVS1-1G > A founded in this family need more study to know its machinism of interrupting P450c17 function.

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.

Classification and pharmacology of progestins.

Besides the natural progestin, progesterone, there are different classes of progestins, such as retroprogesterone (i.e. dydrogesterone), progesterone derivatives (i.e. medrogestone) 17alpha-hydroxyprogesterone derivatives (i.e. chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, megestrol acetate), 19-norprogesterone derivatives (i.e. nomegestrol, promegestone, trimegestone, nesterone), 19-nortestosterone derivatives norethisterone (NET), lynestrenol, levonorgestrel, desogestrel, gestodene, norgestimate, dienogest) and spironolactone derivatives (i.e. drospirenone). Some of the synthetic progestins are prodrugs, which need to be metabolized to become active compounds. Besides the progestogenic effect, which is in common for all progestins, there is a wide range of biological effects, which are different for the various progestins and have to be taken into account, when medical treatment is considered.

Long-term use of progestogens: colon adenoma and colon carcinoma.

Colon cancer is the second most common cancer in women in the Western world and there is a trend towards an increasing risk. Colon adenoma is a potential precursor for colon cancer. Adenoma and carcinoma of the colon seem to be influenced by estrogens and progesterone/progestins. This is related to the presence of estrogen and progesterone receptors, with apparently higher concentrations in colon cancers than in adenomas. Epidemiological data and the finding of a significant reduction in colon cancer risk related to hormone replacement therapy (HRT), and in particular the length of HRT intake, indicate that progesterone/progestins have a preventive effect. This has not been shown with postmenopausal estrogen replacement therapy (ERT) alone. Furthermore, the recurrence rate of adenoma appears to be reduced, and the survival of colon cancer patients improved, with HRT; such effects have not been documented with ERT.

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.

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.

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.

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.

Endocrinology of pregnancy: consequences for the diagnosis and treatment of pregnancy disorders.

Placental human chorionic gonadotropin and corpus luteum secretion of progesterone and oestradiol are the main endocrine events at the beginning of pregnancy, whilst the luteo-placental shift is an important step during the later stages. Progesterone not only affects decidualisation, but is the major immunological determinant and controls uterine contractibility and cervical competence. These properties all contribute considerably towards the correct development of pregnancy and delivery at term.