[Preparing for a pandemic]. / Vorbereitungen auf eine pandemische Welle.

On 16 March 2020 the government of Bavaria declared a state of emergency due to the coronavirus disease 2019 (COVID-19) pandemic. This confronted all clinics with completely new and difficult challenges. In accordance with the official requirements, pandemic officers were appointed at the Kempten Clinic and a clinical management team was established. It was important to keep a relevant proportion of employees off duty at all times, and thus to have a constant reserve available in the event of expected infection-related absences of physicians and nurses. These structural changes were complemented by staff briefings and the creation of a training program on the subject of COVID-19. Within a very short time, algorithms were designed and defined how to manage patients presenting in the hospital or in the emergency room. The surgical program was limited to operations that could not be postponed, such as extrauterine pregnancy or adnexal torsion, and oncological diagnoses without the possibility of primary systemic therapy. In the case of breast cancer, however, therapy was started in all cases in which primary systemic therapy (PST), whether cytotoxic or endocrinological, appeared possible and indicated. As of 1 April 2020, more than 50% of the usable beds in the Kempten Clinic were empty. The utilization of the intensive care unit had also been reduced so that higher numbers of patients requiring artificial respiration could have been cared for at any time.

Ovarian stimulation: from basic science to clinical application.

Treatment for infertility, including ovarian stimulation, was first introduced almost 100 years ago. At this time, radiation therapy became an established treatment, and it was only some decades later that the problem of radiation-induced cancer emerged. Non-human gonadotrophins, such as pregnant mare serum gonadotrophin (PMSG), and human pituitary gonadotrophins (HPG), were commonly used for hormonal stimulation procedures. However, use of PMSG led to antibody formation, and it was therefore only useful for the first treatment cycle. HPG produced good results, but its use came to an end in the late 1980s when it was linked to the development of Creutzfeldt-Jakob disease. The first hormonal product from human menopausal urine to be used was human menopausal gonadotrophin (HMG), followed later by purified preparations of this product. All of these preparations contained a high percentage of unknown urinary proteins, which interfered with batch-to-batch consistency. This changed with the introduction of recombinant gonadotrophins, produced from an immortalized/standardized mammalian cell line (CHO). More recent developments include the introduction of long-acting gonadotrophin formulations. The development of gonadotrophin-releasing hormone (GnRH) analogues and more recently the use of GnRH antagonists has helped to improve ovarian stimulation protocols by optimizing their efficacy, and making them easier to administer.

Multiple pregnancies after assisted reproduction--international comparison.

The high incidence of multiple pregnancies after application of techniques for assisted reproduction is a phenomenon of major concern worldwide. High order multiples in particular have to be regarded as a serious adverse event. However, data show that in Europe, although the situation varies from country to country, multiple births, especially triplet births, as consequence of assisted reproductive technology are on the decline. New strategies such as elective single embryo transfer, emphasized especially by Finland and Sweden, open up new pathways towards safer treatments, reducing the incidence of high order multiples to almost zero while maintaining high pregnancy rates. Compared with Europe, in the US, more than half of all children delivered after assisted reproduction are multiples. While an incidence of 33% of multiple births may seem to be acceptable, an incidence of 54% of children born as multiples, moreover high order multiples, is certainly not. The enormous impact of legal and financial regulations on the attitude of physicians and patients regarding assisted reproduction can be observed at the moment in Germany, with a dramatic decline in number of treatments. However, the incidence of multiples has not increased.

Breastfeeding duration is determined by only a few factors.

BACKGROUND: According to a representative German study prepared between 1996 and 1998 (SuSe-Study) 90% of the mothers were willing to breastfeed, but only 33% (10%) of the babies were exclusively breastfed up to 4 (6) months of age. Bearing in mind that the period currently recommended for breastfeeding is 6 months, this discrepancy highlights the need for action to identify the causes. The present study investigates the behavioural pattern of mothers 4-5 months after delivery. METHODS: The investigation was carried out as a cross-sectional study of mothers who intended to breastfeed their babies (n = 52). All mothers delivered in a hospital, with maximum medical care, and were interviewed later by telephone using a semi-standardised questionnaire. The differences between actual breastfeeding mothers (BF, n = 30) and non-breastfeeding mothers (not BF, n = 22) were identified. The factors influencing decision-making were determined. RESULTS: Significant differences between the two groups tested (BF and not BF) were identified as the perception of the simplicity of breastfeeding, planned pregnancy, marital status, as well as participation at birth preparation classes. If only factors known prior to birth are applied, the decision to breastfeed can be correctly forecast as being 81%. CONCLUSION: In order to allocate consulting resources more effectively, appropriate concepts need to be developed and promoted. If the present results could be verified by a study with a larger sample, the practical use for resource optimisation in breastfeeding consultations would be very beneficial.

Gonadotropin-releasing hormone antagonists for assisted reproductive techniques: are there clinical differences between agents?

Gonadotropin-releasing hormone (GnRH) antagonists have been tested extensively in ovarian stimulation protocols for assisted reproductive techniques (ART). GnRH antagonists immediately and rapidly inhibit gonadotropin release by the anterior pituitary gland by competitive blockage of the GnRH receptor, preventing and interrupting luteinising hormone surges in controlled ovarian hyperstimulation for infertility treatment. A review of the available literature on GnRH antagonists for ART is presented, focusing on the pharmacological and clinical properties of the two compounds available on the market, cetrorelix and ganirelix. Both cetrorelix and ganirelix are well tolerated and effective drugs for controlled ovarian hyperstimulation and are of comparable value for infertility treatment. Cetrorelix is available as a 0.25mg preparation for daily injections and as a 3mg intermediate depot preparation. Ganirelix is available as a 0.25mg preparation for daily injections.Currently, two treatment protocols are used in clinical practice: the GnRH antagonist multiple-dose protocol and the GnRH antagonist single-dose protocol. Both protocols are effective and well tolerated. Cetrorelix and ganirelix have not yet been directly compared in a clinical trial; nor have the single-dose and the multiple-dose approaches been compared in a randomised, controlled trial. Data to compare these compounds in clinical terms can be extrapolated only from results of phase II dose-finding studies and phase III studies comparing GnRH agonist cycles with GnRH antagonists in single- and multiple-dose protocols. Therefore, all conclusions on clinical differences between cetrorelix and ganirelix should remain tentative, as they are based on a limited amount of available data.Randomised, controlled trials comparing cetrorelix and ganirelix are warranted to further evaluate benefits and drawbacks of individual GnRH antagonists. Furthermore, more data are needed to determine the efficacy and safety of cetrorelix and ganirelix in established treatment protocols in patients other than those included in clinical trials investigating new drugs, such as "poor responders", patients with polycystic ovaries, patients with a history of allergy or overweight patients.

Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment.

Replacing GnRH agonist cotreatment for the prevention of a premature rise in LH during ovarian stimulation for in vitro fertilization (IVF) by the late follicular phase administration of GnRH antagonist may render supplementation of the luteal phase redundant, because of the known rapid recovery of pituitary function after antagonist cessation. This randomized two-center study was performed to compare nonsupplemented luteal phase characteristics after three different strategies for inducing final oocyte maturation. Forty patients underwent ovarian stimulation using recombinant (r-)FSH (150 IU/d, fixed) combined with a GnRH antagonist (antide; 1 mg/d) during the late follicular phase. When at least one follicle above 18 mm was observed, patients were randomized to induce oocyte maturation by a single injection of either r-human (h)CG (250 microg) (n = 11), r-LH (1 mg) (n = 13), or GnRH agonist (triptorelin; 0.2 mg) (n = 15). Retrieved oocytes were fertilized by either IVF or intracytoplasmatic sperm injection, depending on sperm quality. Embryo transfer was performed 3-4 d after oocyte retrieval. No luteal support was provided. Serum concentrations of FSH, LH, estradiol (E(2)), progesterone (P), and hCG were assessed at fixed intervals during the follicular and luteal phase. The median duration of the luteal phase was 13, 10, and 9 d for the r-hCG, the r-LH, and the GnRH agonist group, respectively (P = 0.005). The median area under the curve per day (from 4 d post randomization until the onset of menses) for LH was 0.50, 2.34, and 1.07 for the r-hCG, the r-LH, and the GnRH agonist group, respectively (P = 0.001). The median area under the curve per day for P was 269 vs. 41 and 16 for the r-hCG, the r-LH, and the GnRH agonist group, respectively (P < 0.001). Low pregnancy rates (overall, 7.5%; range, 0-18% per started cycle) were observed in all groups. In conclusion, the nonsupplemented luteal phase was insufficient in all three groups. In the patients receiving r-hCG, the luteal phase was less disturbed, compared with both other groups, presumably because of prolonged clearance of hCG from the circulation and the resulting extended support of the corpus luteum. Despite high P and E(2) concentrations during the early luteal phase in all three groups, luteolysis started prematurely, presumably because of excessive negative steroid feedback resulting in suppressed pituitary LH release. Hence, support of corpus luteum function remains mandatory after ovarian stimulation for IVF with GnRH antagonist cotreatment.

Inhibin B on the day of HCG-administration is a predictive factor for failure in assisted reproduction cycles.

MATERIALS AND METHODS: This retrospective study was carried out in order to assess the value of inhibin B as a predictive factor for the assisted reproduction-outcome. Inhibin B on the day of HCG-administration (ovulation induction) was measured in 15 pregnant and 16 non-pregnant patients (defined as positive serum-HCG) and compared by single and multiple logistic regression analysis with classical predictive factors such as estrogen and oocyte number. Both groups were similar with respect to age and cause of infertility. RESULTS: While estrogen, FSH and LH at the HCG-day did not differ, inhibin B, the number of cumulus oocyte complexes and metaphase II -oocytes were statistically significantly different. In a single variable logistic model inhibin B, cumulus oocyte complexes and metaphase II oocytes showed significant correlation with pregnancy. When reassessed in a multiple variable logistic model only inhibin B maintained a considerable influence. Further inspection revealed, that the predictive inhibin B value at HCG-day <1200 pg/ml for failure of ART (assisted reproduction techniques) was 91%. Inhibin >1200 pg/ml showed 70% predictivity for pregnancy. CONCLUSION: In comparison to classical parameters inhibin B at HCG-day seems to be the better prognostic factor for the outcome of ART. Inhibin B <1200 pg/ml seems to be highly predictive for failure of ART.

Gonadotrophin-releasing hormone antagonists: will they replace the agonists?

Modern gonadotrophin-releasing hormone (GnRH) antagonists such as cetrorelix and ganirelix reliably prevent premature LH surges in controlled ovarian hyperstimulation for assisted reproductive technologies. Cetrorelix and ganirelix are safe and effective compounds. Because of their distinct pharmacological mode of action, it has been possible to achieve a significant reduction of treatment time. Fertilization and pregnancy rates are comparable to those obtained in agonist protocols for ovarian stimulation. No allergic or hyperergic reactions have been reported, and patient compliance is excellent. The fact that GnRH antagonists allow an immediate suppression of gonadotrophin concentrations while preserving pituitary responsiveness to endogenous GnRH provides enormous flexibility in treatment. GnRH antagonists have helped to overcome some major disadvantages of GnRH agonists, especially of the long protocol, which is currently the standard protocol for ovarian stimulation. The mistaken administration of antagonists during early pregnancy is not possible, since they are only administered during ovarian stimulation when a premature LH surge may be imminent. They are used in the spontaneous cycle or after pretreatment with oral contraceptives. Pregnancy can easily be ruled out by testing for human gonadotrophic hormone before onset of gonadotrophin stimulation on the second or third day of the cycle. Since flare-up effects are absent, there is no risk of cyst formation. Hormonal withdrawal symptoms are eliminated, since no period of pituitary suppression occurs, and therefore exogenous gonadotrophins are not required. Overall, the duration of the stimulation cycle is as short as a normal menstrual cycle. The procedure seems to be safer than the long protocol, since the most serious complication, the occurrence of severe cases of OHSS, is reduced. It is also safe with respect to the course of pregnancies and the health of offspring. Both protocols developed so far, the single dose and multiple dose antagonist protocol, are comparable, utilizing data from the large prospective phase IIIb studies. Although several studies have indicated a slight reduction in pregnancy rate with GnRH antagonists as compared with agonists, this problem may be rectified by developing flexible antagonist regimens designed for individual patients. Introducing flexible GnRH antagonist regimens should be the area of research in the near future.

Clomiphene-induced LH surges and cetrorelix.

The following rat pituitary cell culture experiments were carried out to find an explanation for the increased premature LH surges in stimulation protocols using clomiphene citrate (CC) and subsequent gonadotrophin with mid-cycle administration of the GnRH antagonist cetrorelix (Cetrotide(R)) in IVF cycles. Rat pituitary cells were pretreated with CC, then stimulated with GnRH with and without co-administration of different concentrations of GnRH antagonist and compared with non-CC-pretreated controls. While lower concentrations of cetrorelix suppressed LH in CC-non-pretreated cells, but not in CC-pretreated cells, higher concentrations of cetrorelix suppressed LH in both groups. CC pretreatment increased the sensitivity of the pituitary for GnRH and reduced the efficacy of subsequent GnRH antagonist. Thus, the elevated risk of premature LH surges in clinical protocols using CC, gonadotrophin and GnRH antagonist could be overcome by increasing the antagonist dose.

Ovarian stimulation: from basic science to clinical application.

Treatment for infertility, including ovarian stimulation, was first introduced almost 100 years ago. At this time, radiation therapy became an established treatment, and it was only some decades later that the problem of radiation-induced cancer emerged. Non-human gonadotrophins, such as pregnant mare serum gonadotrophin (PMSG), and human pituitary gonadotrophins (HPG), were commonly used for hormonal stimulation procedures. However, use of PMSG led to antibody formation, and it was therefore only useful for the first treatment cycle. HPG produced good results, but its use came to an end in the late 1980s when it was linked to the development of Creutzfeldt-Jakob disease. The first hormonal product from human menopausal urine to be used was human menopausal gonadotrophin (HMG), followed later by purified preparations of this product. All of these preparations contained a high percentage of unknown urinary proteins, which interfered with batch-to-batch consistency. This changed with the introduction of recombinant gonadotrophins, produced from an immortalized/standardized mammalian cell line (CHO). More recent developments include the introduction of long-acting gonadotrophin formulations. The development of gonadotrophin-releasing hormone (GnRH) analogues and more recently the use of GnRH antagonists has helped to improve ovarian stimulation protocols by optimizing their efficacy, and making them easier to administer.

Will GnRH antagonists assist in the treatment of benign gynaecological diseases?

While GnRH agonists have become well-established tools for preoperative treatment of uterine fibroids or postoperative treatment in endometriosis for 3-6 months, GnRH antagonists seem to offer important advantages due to their specific pharmacological mode of action. Avoiding any flare-up effect, it seems to be possible to reduce treatment time to about only 2-4 weeks in the case of fibroids to obtain a clinically relevant reduction in size. Furthermore, due to the classic competitive receptor blockade induced by GnRH antagonists, it is feasible to preserve residual oestradiol secretion for a period of 8 weeks in patients with endometriosis. Endometriosis patients undergoing this treatment reported a symptom-free period, with no signs of mood changes, hot flushes, loss of libido, vaginal dryness or other symptoms. Serum oestradiol oscillated around a mean level of 50 pg/ml during therapy. Sequential administration of the GnRH antagonist cetrorelix (Cetrotide), in a 3 mg dosage once weekly over 8 weeks in the case of endometriosis or administration every 4th day for a time span of 2-4 weeks for fibroids, creates a new opportunity for medical treatment. Although 3 mg of cetrorelix acetate obviously acts as an intermediate depot preparation, results obtained so far are very preliminary.

Inhibin A/B in HMG or recombinant FSH ovarian stimulation with cetrorelix medication.

The inhibins are valuable factors in the assessment of the quality of an ovarian stimulation cycle. In spite of good clinical results with recombinant FSH and multiple dose LHRH- antagonist (Cetrotide((R))) administration, there remains a theoretical concern that in cycles stimulated with recombinant FSH, devoid of any LH activity, not enough endogenous LH is available to guarantee good follicle maturation. A total of 287 serum samples from 41 patients was assessed: 20 patients received ovarian stimulation with recombinant FSH, 21 patients with HMG and multiple dose Cetrotide administration. Inhibin A and B were measured on cycle days 2 and 6, the day of HCG administration, the day of embryo transfer as well as 7 and 14 days after the transfer. The two patient groups were similar with regard to age, amount of gonadotrophins required and number of follicles >18 mm and 15-18 mm. Inhibin A and B concentrations were comparable throughout the stimulation, thus indicating the equality of ovarian stimulation with recombinant FSH/HMG and midcyclic antagonist administration. Higher inhibin B concentrations throughout the stimulation were correlated with a higher oocyte yield. The small number of pregnancies prevented assessment of the relationship between inhibin B values and pregnancy rate.