[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.

Urinary steroid profiling in women hints at a diagnostic signature of the polycystic ovary syndrome: A pilot study considering neglected steroid metabolites.

BACKGROUND: Although the polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women with vast metabolic consequences, its etiology remains unknown and its diagnosis is still made by exclusion. This study aimed at characterizing a large number of urinary steroid hormone metabolites and enzyme activities in women with and without PCOS in order to test their value for diagnosing PCOS. METHODS: Comparative steroid profiling of 24h urine collections using an established in-house gas-chromatography mass spectrometry method. Data were collected mostly prospectively. Patients were recruited in university hospitals in Switzerland. Participants were 41 women diagnosed with PCOS according to the current criteria of the Androgen Excess and PCOS Society Task Force and 66 healthy controls. Steroid profiles of women with PCOS were compared to healthy controls for absolute metabolite excretion and for substrate to product conversion ratios. The AUC for over 1.5 million combinations of metabolites was calculated in order to maximize the diagnostic accuracy in patients with PCOS. Sensitivity, specificity, PPV, and NPV were indicated for the best combinations containing 2, 3 or 4 steroid metabolites. RESULTS: The best single discriminating steroid was androstanediol. The best combination to diagnose PCOS contained four of the forty measured metabolites, namely androstanediol, estriol, cortisol and 20ßDHcortisone with AUC 0.961 (95% CI 0.926 to 0.995), sensitivity 90.2% (95% CI 76.9 to 97.3), specificity 90.8% (95% CI 81.0 to 96.5), PPV 86.0% (95% CI 72.1 to 94.7), and NPV 93.7% (95% CI 84.5 to 98.2). CONCLUSION: PCOS shows a specific 24h urinary steroid profile, if neglected metabolites are included in the analysis and non-conventional data analysis applied. PCOS does not share a profile with hyperandrogenic forms of congenital adrenal hyperplasias due to single steroid enzyme deficiencies. Thus PCOS diagnosis by exclusion may no longer be warranted. Whether these findings also apply to spot urine and serum, remains to be tested as a next step towards routine clinical applicability.

Osteoporosis drug treatment: duration and management after discontinuation. A position statement from the SVGO/ASCO.

Antiosteoporotic drugs are recommended in patients with fragility fractures and in patients considered to be at high fracture risk on the basis of clinical risk factors and/or low bone mineral density. As first-line treatment most patients are started with an antiresorptive treatment, i.e. drugs that inhibit osteoclast development and/or function (bisphosphonates, denosumab, oestrogens or selective oestrogen receptor modulators). In the balance between benefits and risks of antiresorptive treatment, uncertainties remain regarding the optimal treatment duration and the management of patients after drug discontinuation. Based on the available evidence, this position statement will focus on the long-term management of osteoporosis therapy, formulating decision criteria for clinical practice.

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.

[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.

Vaginal prolapse, pelvic floor function, and related symptoms 16 years after sex reassignment surgery in transsexuals.

OBJECTIVE: To evaluate the prevalence of prolapse and related bladder, bowel, and sexual problems in transsexual patients (TS) after sex reassignment surgery. DESIGN: A cross-sectional study. SETTING: A tertiary referral center. PATIENT(S): 55 transsexuals, comprising 52 male-to-female and 3 female-to-male patients. INTERVENTION(S): Gynecologic examination with pelvic floor testing, measurements for pelvic organ prolapse applying International Continence Society pelvic organ prolapse (ICS-POP) staging, and the Sheffield prolapse questionnaire to assess prolapse symptoms, and bladder, bowel, and sexual function. MAIN OUTCOME MEASURE(S): ICS-POP score and Sheffield prolapse questionnaire. RESULT(S): Of the 55 transsexuals who participated in this study (52 male-to-female and 3 female to male), 7.5% showed a prolapse greater than or similar to ICS-POP stage 2, and 3.8% required surgical intervention. For bladder symptoms, 47% reported voiding difficulties, 24.6% urgency, 17% urge incontinence, and 23% stress incontinence. Fecal urgency and incomplete emptying of the bowel occurred in 9.4% and 7.6% of patients, respectively. In addition, 23% reported that they were never satisfied with their sexual function. CONCLUSION(S): Pelvic floor symptoms may occur in transsexuals involving the bladder, bowel, and sexual function. Surgical corrective options should be determined on an individual basis as with other patients who have prolapse symptoms.

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.

[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 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.

[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.

Quality of life 15 years after sex reassignment surgery for transsexualism.

OBJECTIVE: To evaluate quality of life and patients' satisfaction in transsexual patients (TS) after sex reassignment operation compared with healthy controls. DESIGN: A case-control study. SETTING: A tertiary referral center. PATIENT(S): Patients after sex reassignment operation were compared with a similar group of healthy controls in respect to quality of life and general satisfaction. INTERVENTION(S): For quality of life we used the King's Health Questionnaire, which was distributed to the patients and to the control group. Visual analogue scale was used for the determination of satisfaction. MAIN OUTCOME MEASURE(S): Main outcome measures were quality of life and satisfaction. RESULT(S): Fifty-five transsexuals participated in this study. Fifty-two were male-to-female and 3 female-to-male. Quality of life as determined by the King's Health Questionnaire was significantly lower in general health, personal, physical and role limitations. Patients' satisfaction was significantly lower compared with controls. Emotions, sleep, and incontinence impact as well as symptom severity is similar to controls. Overall satisfaction was statistically significant lower in TS compared with controls. CONCLUSION(S): Fifteen years after sex reassignment operation quality of life is lower in the domains general health, role limitation, physical limitation, and personal limitation.

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.

Anti-Müllerian hormone and inhibin B as predictors of pregnancy after treatment by in vitro fertilization/intracytoplasmic sperm injection.

OBJECTIVE: To evaluate anti-Müllerian hormone (AMH) as a marker of reproductive outcome after IVF/intracytoplasmic sperm injection (ICSI). DESIGN: Longitudinal study. SETTING: University hospital. PATIENT(S): Two hundred seventy-six consecutive women undergoing IVF/ICSI. INTERVENTION(S): Ovarian stimulation, oocyte retrieval, IVF, ICSI, embryo transfer, AMH, and inhibin B determinations in serum and follicular fluid (FF). MAIN OUTCOME MEASURE(S): The AMH and inhibin B concentrations in 276 matched FF/serum pairs have been determined. Different outcome groups have been compared and set in relation to the oocyte count, morphological parameters, and steroid hormone levels. RESULT(S): The concentrations of AMH and inhibin B in both serum and FF were significantly higher in the group of women who became pregnant in the corresponding treatment cycle than in those who did not conceive. Positive correlations were observed between serum inhibin B concentrations and embryo morphology (r = 0.126, 95% confidence interval 0.026-0.284). Serum and FF AMH or inhibin B correlated positively with the oocyte count and negatively with the pretreatment cycle day 3 FSH level and the total administered gonadotropin dose. CONCLUSION(S): The AMH and inhibin B levels on the day of oocyte retrieval are correlated to reproductive outcome.

Statistically significant changes of antimüllerian hormone and inhibin levels during the physiologic menstrual cycle in reproductive age women.

OBJECTIVE: To define the dynamics of antimüllerian hormone (AMH) and inhibins during the physiologic menstrual cycle. DESIGN: Longitudinal study. SETTING: University hospital. PATIENT(S): 36 young, healthy, normal weight Caucasian women without medication. INTERVENTION(S): Normal ovulatory menstrual cycles were evaluated by regular blood sampling taken every other day and periovulatory every day. MAIN OUTCOME MEASURE(S): Serum concentrations of AMH, inhibin A and B, follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, estradiol, progesterone, and free testosterone were measured in all blood samples. RESULT(S): Median AMH levels are statistically significantly higher in the late follicular compared with ovulation or the early luteal phase. There are statistically significant correlations between both AMH and FSH, and AMH and free testosterone in all cycle phases. Inhibin A increases strongly in the late follicular phase and peaks at day LH + 4. Inhibin B shows a broad midfollicular and a sharp early luteal peak, the difference being statistically significant between day LH + 4 and the earlier time points and between day LH + 2 and day LH. Although there is a negative association between inhibin A or B and the body mass index (BMI), there is no correlation between AMH and the BMI. CONCLUSION(S): Levels of AMH show a statistically significant change during the menstrual cycle and may influence the circulating gonadotropin and steroid hormone levels.