[Contraception in Women at Risk]. / Kontrazeption bei Risikopatientinnen.

Contraception in Women at Risk Abstract. Healthy non-obese non-smokers without personal contraindications may use all hormonal and non-hormonal contraceptive methods up to the normal menopausal age. However, underlying diseases or an unfavourable lifestyle may change this liberty of choice. Vascular risks are potentiated by age, obesity, smoking, arterial hypertension, and diabetes. The presence of any arterial disease is an absolute contraindication against combined oral contraceptive (CHC). In regard of internal diseases, CHC possess the highest risk for serious complications among the methods known to be safe, whereas the lowest risk is seen in users of Cu-IUDs. The hormonal alternatives to CHC are gestagen-only preparations including levonorgestrel-releasing IUS. If no further pregnancies are intended, sterilisation of one of the partners is also a valid alternative. Because of their lack of reliability, barrier methods and natural family planning should be strongly discouraged in women with an underlying disease. Any unplanned pregnancy may present a high risk for mother and child. In presence of an underlying disease, it is strongly recommended to consult the treating specialist before a hormonal method is chosen. Independently of the method used, all women at risk for sexually transmitted diseases should also use a barrier method.

[Menopausal Hormone Therapy in women with other underlying diseases: how to proceed?] / Kurzreview: Internistische Erkrankungen und Menopausale Hormontherapie.

Menopausal Hormone Therapy in women with other underlying diseases: how to proceed? Abstract. Postmenopausal women frequently suffer, in addition to classical climacteric symptoms, from other diseases. Therefore, it is important to know when, in which form, and with which dosage menopausal hormone therapy (MHT) may be prescribed with regard to the underlying chronic disease. All women's health specialists have to know when MHT is contraindicated. To minimize the risks of MHT in the presence of a chronic disease, the following basic rules should be kept in mind: If there is no absolute contraindication, MHT should be started within the "window of opportunity" (age < 60 years or within 10 years of menopause). Continuous transdermal administration has to be preferred; in the presence of most chronic diseases, a hepatic first pass effect should be avoided. The lowest efficient dosage should be selected because most side effects are dose dependent. Cyclical fluctuations of hormone blood levels should be avoided. Metabolically neutral progestagens, such as micronized progesterone, dydrogesterone and dienogest or transdermal administration of norethisterone acetate (NETA) should be chosen. Medroxyprogesterone acetate has to be avoided. If there are doubts, the treating physician should be contacted. Angiopathies (e. g., in arterial hypertension, diabetes mellitus, lupus erythomatodes) are an absolute contraindication for MHT. In the absence of angiopathies, transdermal MHT might be prescribed in women suffering from these diseases after an extensive risk-benefit evaluation and in agreement with the treating physician.

[Climacteric depression and anxiety]. / Depressionen und Angstzustände im Klimakterium.

Climacteric depression and anxiety Abstract. Women of all ages have a higher incidence of depression than men. The lifetime prevalence of depressive disorders in women is twice the prevalence in males and amounts to 18 - 21 %. The menopausal transition is a "window of increased vulnerability" and might trigger a depressive disorder. In this period, the risk to get depressive is 1.5 - 4 times higher than in the premenopause, particularly in women suffering from vasomotor symptoms and presenting additional risk factors for mood disorders and depression. Depression in climacteric women is still underestimated and has to be actively looked for by family doctors and gynaecologists. Oestrogens modulate the metabolism of serotonin and noradrenalin, as do SSRI / SNRI and antidepressants, and influence therefore mood, mental function and cognition. In the menopausal transition, there is suggestive evidence that Oestrogen therapy can improve mood, anxiety and depression. In peri- and early postmenopausal women with climacteric vasomotor symptoms, Oestrogens might be considered as a first-line treatment for depressive symptoms. However, Oestrogens do not improve depression in the late postmenopause. In depressed elderly postmenopausal women without hot flushes, SSRI / SNRI and antidepressants remain the first-line treatment. Each pharmacological treatment should always be embedded in a global therapeutic concept including among others frequently psychotherapy and social measures.

Consensus: soy isoflavones as a first-line approach to the treatment of menopausal vasomotor complaints.

The association between an increased uptake of isoflavones and a reduced frequency of menopausal hot flushes was first described in 1992, based on a lower incidence of hot flushes in countries with a high consumption of soy. Since then, numerous clinical trials with various sources of isoflavones including soy and red clover have been presented, with practically all of the studies with adequate design delivering an outcome in favour of isoflavone supplementation. An in-depth risk assessment (EFSA 2015) concludes that the amply available human data does not indicate any suspected harmful effects from a potential interaction of isoflavones with hormone-sensitive tissues in the mammary gland, the uterus and the thyroid gland. Safety was ascertained with long-term intake of up to 150 mg isoflavones per day ingested for the duration of at least 3 years. Moreover, high isoflavone intake was found to have preventive effects with respect to breast cancer. Clinical findings indicate potential benefits of isoflavone exposure even during breast cancer treatment with tamoxifen or anastrozole.

Menopause - wann und wie therapieren?

The publication of the first report of the Women's Health Inititiave in 2002, which evaluated the efficacy and the risks of substitution of postmenopausal women with estrogens and gestagens, has exerted a profound negative impact on the utilization of hormonal treatment. On the one hand, the WHI-studies have left both the medical community and the patients community in a state of anxiety and uncertainty, on the other has an entire set of differentiated and clarifying post hoc analyses contributed to re-define the role and the safety of hormonal treatment of menopausal women and the preventive effect on osteoporotic fractures has remained uncontested. As a result, new protocols based on lower dosages with new combinations of endocrine products allow for an early start of hormonal substitution in menopause within the so-called "window of opportunity" thereby not only ameliorating the climacteric symptoms but also preventing the early onset of cardiovascular disease. In addition, the risk of invasive breast cancer can now be better quantified, whereas participation in a mammographic screening programme helps to improve the safety of the treatment.

Ethical issues in human reproduction: Protestant perspectives in the light of European Protestant and Reformed Churches.

Protestantism is not a centralized religion. It is composed by many independent Churches having different moral and ethical standards. This review concentrates on the ethical principles prevalent in most modern European Reformed Churches. It does not intend to discuss the ethical principles of many other Protestant Churches present mainly in the USA. The common foundations of Protestant theology are the "five sola ("Sola scriptura", Sola fide", "Sola gratia", Solus Christus or Solo Christo", "Soli deo gloria"). In opposition to the Catholic Church, no intermediary is needed between the Bible and the believer. As a consequence, Protestant Churches have no Magisterium, such as the Catholic Church. Therefore Protestant Churches cannot declare a certain position to be the "official position". Each Christian is personally responsible for all his acts, including his ethical behaviour. There is no complete unanimity among all Protestants on ethics or on any other issue. Human dignity, personal rights and self-determination have to be respected in each ethical consideration. The supersession of the Old Mosaic Covenant (including traditional Jewish law or Halakhah, maintained in Catholicism) by the New Covenant and by Christian Theology has an important impact on Protestant ethics in reproductive medicine. In the New Covenant, the Protestants Churches did not maintain the mandatory obligation from the old Mosaic Covenant to be fruitful and to multiply: there is no divine obligation by God to procreate. As a consequence, contraception is not a sin and not unethical. The status of the embryo is the key for the ethical consideration of all methods used in reproductive medicine. Most representatives of modern Protestant theology and bioethics defend the opinion that the embryo is not an independent human being as is the newborn child. For most Protestant bio-ethicists, as long as an embryo has no nervous system, no organs and no pain receptors, it cannot be seen as a human being sensu strictiori: the zygote is not yet a "human being". The ethical right to be protected prenatally increases gradually with the age and the development of the embryo. Following this so-called gradualist interpretation, the early stages of an embryo merit ethically a special status: although they have already "human life", they are not yet a "human being". All ethical considerations in modern reproductive medicine discussed in this review are based on this concept of the status of the embryo. It depends largely on the acceptance or rejection of this special status of the embryo, if a Protestant considers a certain method in reproductive medicine to be ethical or unethical.

Randomized controlled trial comparing highly purified (HP-hCG) and recombinant hCG (r-hCG) for triggering ovulation in ART.

BACKGROUND: A randomized controlled trial (RCT) comparing highly purified human Choriogonadotrophin (HP-hCG) and recombinant hCG (r-hCG) both administered subcutaneously for triggering ovulation in controlled ovarian stimulation (COS) for Assisted Reproductive Technology (ART). METHODS: Multi-centre (n = 4), prospective, controlled, randomized, non-inferiority, parallel group, investigator blind design, including 147 patients. The trial was registered with www.clinicaltrials.gov, using the identifier: NCT00335569. The primary endpoint is the number of oocytes retrieved, while the secondary endpoints include embryo implantation, pregnancy and delivery rates as well as safety parameters. RESULTS: The number of retrieved oocytes was not inferior when HP-hCG was used as compared to r-hCG: the mean number was 13.3 (6.8) in HP-hCG and 12.5 (5.8) in the r-hCG group (p = 0.49) with a 95% CI (-1.34, 2.77). Regarding the secondary outcomes, there were also no differences in fertilization rate at 57.3% (467/815) vs. 61.3% (482/787) (p = 0.11), the number of embryos available for transfer and cryopreservation (2PN stage) and implantation, pregnancy and delivery rates. Furthermore, there were no differences in the number and type of adverse events reported. HP-hCG was therefore not inferior to r-hCG. CONCLUSIONS: HP-hCG and r-hCG are equally efficient and safe for triggering ovulation in ART and, both being administered subcutaneously, equally practical and well tolerated by patients.

[Selective Estrogen Receptor Modulators (SERMs) for prevention and treatment of postmenopausal osteoporosis]. / Selektive Östrogen-Rezeptormodulatoren (SERMs) zur Prävention und Therapie der Postmenopausalen Osteoporose.

The three modern Selective Estrogen Receptor Modulators (SERMs) Raloxifene, Lasoxifene and Bazedoxifene registered in Europe reduce in postmenopausal women with a high risk for osteoporosis the incidence of vertebral fractures by 30 - 50 %, depending on the subgroup they belong to. Solid prospective fracture data for risk reduction in non-vertebral fractures, including the hip, are missing for Raloxifene and Bazedoxifene. However, a post hoc analysis suggests that the risk for non-vertebral fractures is significantly reduced by Raloxfene in women with severe osteoporosis. The simultaneous decrease of the incidence of ER-positive invasive breast cancer in Raloxifene users is highly relevant for clinicians. Unfortunately, Raloxifene and Bazedoxifene are, in the EU and in Switzerland, only labelled for the use in the prevention and treatment of postmenopausal osteoporosis. SERMs may induce or augment vasomotor symptoms. Therefore, SERMs are not a first line therapy in early postmenopause. Looking at other hormonal options, Hormone Replacement Therapy (HRT) remains the first line therapy for fracture reduction in the peri- and early postmenopause. SERMs are an appropriate choice for the continuation of fracture prevention after an initial HRT, particularly for the prevention of vertebral fractures. SERMs are safe if (as in oral HRT) the slightly increased risk for venous thrombo-embolism is respected. In conclusion, SERMs have today their well established place in the prevention and treatment of postmenopausal osteoporosis, particularly in women with a simultaneously increased breast cancer risk.

Serum glycodelin pattern during the menstrual cycle in healthy young women.

OBJECTIVE: Glycodelin (PP14) is produced by the epithelium of the endometrium and its determination in the serum is used for functional evaluation of this tissue. Given the complex regulation and the combined contraceptive and immunosuppressive roles of glycodelin, the current lack of normal values for its serum concentration in the physiological menstrual cycle, derived from a large sample number, is a problem. We have therefore established reference values from over 600 sera. DESIGN: Retrospective study using banked serum samples. SETTING: University hospital. METHODS: Measurement of blood samples daily or every second day during one full cycle. MAIN OUTCOME MEASURES: Serum concentrations of glycodelin and normal values for every such one- or two-day interval were calculated. Late luteal phase glycodelin levels were compared with ovarian hormones. Follicular phase levels were compared with stimulated cycles from patients undergoing in vitro fertilization. RESULTS: Glycodelin concentrations were low around ovulation. Highest levels were observed at the end of the luteal phase; the glycodelin serum peak was reached 6-8 days after the one for progesterone. Late luteal glycodelin levels correlated negatively with the body mass index and positively with the progesterone level earlier in the secretory (mid-luteal) phase in the same woman. No associations with other ovarian hormones were observed. Follicular phase glycodelin levels were higher in the spontaneous than in the in vitro fertilization cycles. CONCLUSIONS: Normal values taken at two- or one-day intervals demonstrate the very late appearance of high serum glycodelin levels during the physiological menstrual cycle and their correlation with progesterone occurring earlier in the cycle.

[Antipsychotics and hyperpolactinaemia: pathophysiology, clinical relevance, diagnosis and therapy]. / Antipsychotika und Hyperprolaktinämie: Pathophysiologie, klinische Bedeutung, Abklärung und Therapie.

Hyperprolactinaemia is a frequent but often neglected side effect of typical, but also of many atypical antipsychotics such as amisulpiride, risperidone or ziprasidone. Besides galactorrhoea, potential consequences are suppression of the hypothalamic-pituitary-gonadal axis with hypogonadism, sexual dysfunction, infertility and in women also irregularities of the menstrual cycle and amenorrhoea. Potential long term consequences are mainly osteopenia and osteoporosis with an enhanced risk of fractures. Hyperprolactinaemia, if not clearly caused by a prolactin inducing antipsychotic, should always be thoroughly investigated. Ideally, prolactin should be measured before starting a patient on a new antipsychotic. Furthermore, before neuroleptic treatment is begun, and also in regular intervals after that, patients should be asked about potential clinical signs of hyperprolactinaemia. Hyperprolactinaemia which is clearly due to antipsychotics but without clinical symptoms only requires regular controls of bone mineral density. However, if clinical symptoms occur, switching to a prolactin sparing antipsychotic may be necessary. In these cases fertility is often regained and the women concerned have to be informed about the enhanced risk of pregnancy and counselled regarding contraception. If switching is not possible, estradiol has to be substituted in women. Also in men with hypogonadism hormonesubstitution (with testosterone) is usually indicated. Generally hyperprolactinaemia in psychiatric patients should be taken more seriously in the future.

[Progestagen use in oral contraception - basic knowledge]. / Grundlagen zur Gestagen-Komponente in der hormonalen Kontrazeption.

The effects of most prostagens used in hormone replacement therapy (HRT) and in hormonal contraception are not identical. They differ in their structure, the metabolisation, their bioavailability and their partial activities. Therefore, it does not make any sense to declare that the different progestagens with their different profiles belong to one class of substances, having all the same effect. In function of their partial activities, progestagens are used today specifically for HRT, for hormonal contraception or as an anti-androgen. Because of their metabolic profile, some newer progestagens can be considered to be specifically favourable, such as Norpregnanes, Dienogest and Drospirenone. This review summarizes the properties and partial activities of progestagens used today and analyzes its clinical consequences.

[Long-cycle treatment in oral contraception]. / Langzyklus bei Ovulationshemmern.

Surveys show that most women desire a change in their menstrual pattern in the sense that they would prefer less menstruations or even amenorrhea. On this behalf, there is no difference between women having spontaneous natural cycles and women taking the pill. The main reasons are less menstrual bleedings, better hygienic conditions, a better quality of life and less blood loss. In women wanting regular monthly periods, the opinion is dominant that suppression of menstrual bleedings is "unnatural". It is therefore primordial to inform women that contraceptive safety is even increased in users following the long-cycle principal and that a fertility decrease has not to be feared. The benefit of the long-cycle OC is a reduction of the hormonal fluctuations induced by the pill-free interval with its consecutive somatic and mental symptoms, as well as an increased contraceptive safety. The following cycle- and menstruation-dependent symptoms as listed as an indication for the long-cycle use: Endometriosis, hypermenorrhea, dysmenorrhea, hemorrhagic diathesis, uterine fibroma, polyzystic ovary syndrome, migraine due to estrogen-deficiency in the pill-free interval as well as premenstrual syndrome.

[Contraception in women with special problems]. / Kontrazeption bei Problemfällen.

Thromboembolic, cardiovascular and cerebrovascular events are age-dependent. They are extremely rare in young women. In contrast to the progestogen-only pills, oral contraceptives (OC) increase the risk of venous thrombosis. However, decisive ist the genetic predisposition. In healthy non-smokers of less than 35 years of age, the risk to suffer from a myocardial infarction or a cerebrovascular accident is not increased by OC. Risk factors play a major role in the etiology of cardiovascular diseases. A detailed personal and family history is therefore mandatory before OC are prescribed. Very rarely, blood pressure is increased by OC. Although the incidence of such an increase is very low, blood pressure has to be measured regularly in pill users. Inspite of a current opinion, weight increase is rare in OC users. It depends mainly on the individual predisposition. An increased water retention can be reduced by a combined OC containing a progestagen with an antimineralocorticoid activity. Changes in insulin and blood sugar induced by low-dose OC are minimal so that they have no clinical relevance. OC do not increase the incidence of diabetes. Adrenal and thyroid function are not influenced by OC, there is no increased incidence of prolactinomas. Asthma is no contraindication against OC. If there is a cycle-dependent aggravation of the disease, OC might be beneficial. OC have no side-effects on the eye or the ear. In women suffering from lupus erythematodes having no renal participation, no increased antiphospholipid-antibodies and showing a stable or inactive disease, low-dose OC might be used.

[Does hormonal contraception increase the risk for tumors?]. / Erhöht die hormonale Kontrazeption das Tumorrisiko?

A non-contraceptive benefit of oral hormonal contraceptives (OC) is a diminished risk for certain benign as well as malignant tumours, such as benign breast tumours, uterine fibroids and ovarian cysts. Endometriosis itself is not positively influenced by OC, but dysmenorrhea is decreased. Modern low-dose OC do not increase the risk of liver cell adenomata or carcinomata. OC do not influence melanoma. Modern data do not suggest an increased risk for breast carcinoma in OC users. Long-term use of OC leads to a decreased risk of endometrial and colorectal carcinomata. Cervical carcinoma is not influenced directly by OC, but probably indirectly through a change in sexual behaviour. There is no increase of vulvar or vaginal carcinoma, even after long-term use of OC.

[Oral contraception - doses and way of administration]. / Hormonale Kontrazeption - Dosierung und Verabreichungsformen.

Since the correlation between the amount of Ethinylestradiol (EE) and the thromboembolic risk has been recognized, the development of new oral contraceptives (OC) has been characterized by a constant lowering of the EE dosage. The consecutive decrease of ovulation inhibition has been compensated by the introduction of potent progestagens. Therefore, the contraceptive safety has been maintained in presence of less side-effects. The effect of ultra-low-dose OC on acne and seborrhea remains beneficial. The effect of ultra-low-dose OC on bone is contradictory. Because there are fundamental differences between Estradiol and EE, the thromboembolic risk is not decreased by the parenteral administration of EE. In users of the contraceptive patch, it is even increased. EE is not bound at SHBG. Because of its Ethinyl group, the inactivation of EE occurs slowly. Therefore, EE reaches the liver in a low but constant concentration where it modifies many estrogen-dependent hepatic parameters significantly. One of these is hemostasis. It is generally accepted that such changes are responsible for the increased thromboembolic risk of the contraceptive patch and vaginal ring. A reduction of the hormone-free interval of the pill to 5 or 4 days results in a complete suppression of the ovarian function, a reliable ovulation inhibition and an increase of the contraceptive efficacy in spite of a reduction of the EE dosage to 20 microg or 15 microg.

[Contraception in adolescence and perimenopause]. / Kontrazeption zu Beginn und Ende der fertilen Lebensphase.

The risk-benefit-ratio of hormonal contraception (OC) is positive in adolescents as well as in women over 40 years of age if some essential rules are respected. In adolescents, the acquirement of a normal peak bone mass has to be guaranteed by the use of the OC. The dosage of the OC has to be adapted individually to the basic hormonal situation. In women over 40, contraindications such as hypertension, obesity, smoking or dyslipidemia have to be actively excluded. In both groups of age, the risk of a correctly indicated OC is inferior to the risk of an unwanted pregnancy.

Gene expression in cultured endometrium from women with different outcomes following IVF.

Estradiol and progesterone are crucial for the acquisition of receptivity and the change in transcriptional activity of target genes in the implantation window. The aim of this study was to differentiate the regulation of genes in the endometrium of patients with recurrent implantation failure (IF) versus those who became pregnant after in vitro fertilization (IVF) treatment. Moreover, the effect of embryo-derived factors on endometrial transcriptional activity was studied. Nine women with known IVF outcome (IF, M, miscarriage, OP, ongoing pregnancy) and undergoing hysteroscopy with endometrial biopsy were enrolled. Biopsies were taken during the midluteal phase. After culture in the presence of embryo-conditioned IVF media, total RNA was extracted and submitted to reverse transcription, target cDNA synthesis, biotin labelling, fragmentation and hybridization using the Affymetrix Human Genome U133A 2.0 Chip. Differential expression of selected genes was re-analysed by quantitative PCR, in which the results were calculated as threshold cycle differences between the groups and normalized to Glyceraldehyde phosphate dehydrogenase and beta-actin. Differences were seen for several genes from endometrial tissue between the IF and the pregnancy groups, and when comparing OP with M, 1875 up- and 1807 down-regulated genes were returned. Real-time PCR analysis confirmed up-regulation for somatostatin, PLAP-2, mucin 4 and CD163, and down-regulation of glycodelin, IL-24, CD69, leukaemia inhibitory factor and prolactin receptor between Op and M. When the different embryo-conditioned media were compared, no significant differential regulation could be demonstrated. Although microarray profiling may currently not be sensitive enough for studying the effects of embryo-derived factors on the endometrium, the observed differences in gene expression between M and OP suggest that it will become an interesting tool for the identification of fertility-relevant markers produced by the endometrium.