Diagnosis and Therapy of Female Genital Malformations (Part 1). Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Registry Number 015/052, May 2019).

Objectives Female genital malformations may take the form of individual entities, they may involve neighboring organs or they may occur in the context of complex syndromes. Given the anatomical structures of the vulva, vagina, uterus and adnexa, the clinical picture of malformations may vary greatly. Depending on the extent of the malformation, organs of the urinary system or associated malformations may also be involved. Methods This S2k-guideline was developed by representative members from different medical specialties and professions as part of the guidelines program of the DGGG, SGGG and OEGGG. The recommendations and statements were developed using a structured consensus process with neutral moderation and voted on. Recommendations The guideline is the first comprehensive presentation of the symptoms, diagnosis and treatment options for female genital malformations. Additional chapters on classifications and transition were included.

Diagnosis and Therapy of Female Genital Malformations (Part 2). Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Registry Number 015/052, May 2019).

Objectives Female genital malformations may be present in the form of individual entities, they may involve neighboring organs or they may occur in the context of complex syndromes. Given the anatomical structures of the vulva, vagina, uterus and uterine appendages, the clinical picture of malformations varies greatly. Methods This S2k-guideline was developed by representative members from different medical specialties and professions as part of the guidelines program of the DGGG, SGGG and OEGGG. The recommendations and statements were developed and voted on using a structured consensus process with neutral moderation. Recommendations This guideline is the first comprehensive summary of female genital malformations from infancy to adulthood which covers clinical examinations, diagnostic workups and treatment options. Additional chapters have been included on complex urogenital malformations, vascular malformations, psychosomatic care, and tumor risk.

Endometriosis patients in the postmenopausal period: pre- and postmenopausal factors influencing postmenopausal health.

OBJECTIVE: To evaluate patients' health status and the course of endometriosis from the premenopausal to the postmenopausal period and evaluate influencing factors that may be relevant. METHODS: Questionnaire completed by 35 postmenopausal women in whom endometriosis had been histologically confirmed premenopausally. Correlation and regression analyses were carried out to identify factors relevant to their postmenopausal health status. RESULTS: Overall, there was clear improvement in typical endometriosis symptoms and sexual life. Clear associations (P < 0.005) were observed between premenopausal factors like physical limitations caused by the disease, impaired social contacts and psychological problems, and postmenopausal pain and impairment of sexual life. Three statistical models for assessing pain and impairment of sexual life in the postmenopausal period were calculated on the basis of clinical symptoms in the premenopausal period, with a very high degree of accuracy (P < 0.001; R(2) = 0.833/0.857/0.931). CONCLUSIONS: The results of the survey strongly suggest that physical fitness and freedom from physical restrictions, a good social environment, and psychological care in both the premenopausal and postmenopausal periods lead to marked improvements in the postmenopausal period with regard to pain, dyspareunia, and influence on sexual life in endometriosis patients.

Allen-Masters syndrome: do the classic risk factors also apply in patients with endometriosis?

AIM: To evaluate whether the classic risk factors for Allen-Masters syndrome, such as body mass index (BMI) and spontaneous births, are in fact responsible for the condition in patients with endometriosis. METHODS: A total of 26 women who underwent a laparoscopic procedure due to chronic pelvic pain, Allen-Masters syndrome and endometriosis from 2009-2011 were enrolled in this study from an endometriosis competence center specializing in minimally invasive surgery. This was a retrospective cohort study (Canadian Task Force classification II-2). RESULTS: Only eight of the 26 patients (30.77%; 95% confidence interval [CI], 14.33-51.79%) had the classic risk factors (BMI >25 kg/m(2) and/or at least one spontaneous birth). The mean age in the study group was 32.08 years (SD ± 5.45). The patients had a mean BMI (kg/m(2) ) of 19.61 (SD ± 3.07). The means for the patients' clinical data were 0.88 (SD ± 1.53) pregnancies, 0.81 (SD ± 1.23) for parity, 0.27 (SD ± 0.60) for cesareans and 0.54 (SD ± 0.99) for spontaneous births. The revised American Society for Reproductive Medicine (rASRM) stage showed a median of grade III. The left side of the posterior compartment was more often affected (73.1% of cases) than the right side in all patients. CONCLUSION: In all, 69.23% of the cases (95% CI, 48.21-85.67%) were not explained by the classic risk factors. In view of the absence of other diseases and otherwise unremarkable parameters, we consider mechanical damage of the lesser pelvis not to be solely responsible for AMS. Further observations in patients with AMS, with and without endometriosis, may be able to contribute to research into the actual etiology of the condition.

Endometriosis: a premenopausal disease? Age pattern in 42,079 patients with endometriosis.

PURPOSE: The objectives of this study were to examine the age distribution among women suffering from endometriosis and to establish that endometriosis is not a disease that occurs only in premenopausal women. The null hypothesis was that there are also postmenopausal women with endometriosis. METHODS: In a retrospective epidemiological study, a descriptive analysis of data from the Federal Statistical Office in Germany for 2005 and 2006 was carried out. A total of 42,079 women in Germany were admitted for surgical treatment due to histologically confirmed endometriosis during this period. The patients' age distribution was examined and they were assigned to 5-year age groups and then to premenopausal, perimenopausal, and postmenopausal subgroups. RESULTS: A total of 20,835 women in 2005 and 21,244 in 2006 were admitted to hospital for the treatment of endometriosis. In the premenopausal group (age 0-45 years), there were 33,814 patients (80.36 %); 23 patients (0.05 %) in this premenopausal group were younger than 15. There were 7,191 patients (17.09 %) in the perimenopausal group (45-55 years), and the postmenopausal group (55-95 years) included 1,074 patients (2.55 %). CONCLUSIONS: The assumption that endometriosis is a disease of the premenopausal period and in women of reproductive age needs to be called into question, as well as the influence of estrogen in fully developed endometriosis. Due to the relatively high prevalence of the condition in patients aged over 40, physicians should consider endometriosis in cases of unclear pelvic pain in this age group.

Assessment of FSHR variants and antimüllerian hormone in infertility patients with a reduced ovarian response to gonadotropin stimulation.

OBJECTIVE: To study women with a poor response to ovarian hormone stimulation, known as low responders. Genetic defects in the FSH receptor gene (FSHR) were analyzed as well as antimüllerian hormone (AMH) for ovarian reserve. DESIGN: Retrospective cohort study. SETTING: University hospital. PATIENT(S): Two hundred fifty-nine patients total: 74 low responders; 88 patients receiving assisted reproduction therapy (ART) with a normal ovarian response; and 97 women with a normal fertility status. INTERVENTION(S): DNA from patients was analyzed using real-time polymerase chain reaction. Serum concentrations of AMH were assessed using ELISA. MAIN OUTCOME MEASURE(S): The FSHR variants Asn680Ser (rs6166), Ala189Val (rs121909658), Ile160Thr (rs121909659), Thr449Ile (rs28928870) and the serum AMH concentrations were assessed. RESULT(S): With the exception of the frequent Asn680Ser polymorphism, no homozygotic SNPs of FSHR were found. In the group of ART patients, Thr160/Ile160 variants were more frequent in comparison with women with normal fertility. The Ser680/Ser680 was more frequent in ART patients than in women with normal reproductive function. The rate of live births was markedly reduced, particularly in the low responder group. No difference was noted in the distribution of the Ala189Val and Thr449Ile variant. Low serum AMH values were observed in 75% of the low responder group. CONCLUSION(S): FSHR gene variations such as Asn680Ser, Ala189Val, Thr449Ile, and Ile160Thr did not seem to be a decisive factor of poor response to fertility treatment, whereas the low ovarian reserve determined by AMH is considered more crucial.

Blood group A: an overseen risk factor for early-onset ovarian hyperstimulation syndrome?

Ovarian hyperstimulation syndrome (OHSS), a potentially life-threatening complication, is classified into two distinct forms, early-onset and late-onset OHSS. Few risk factors have been established, but no association with ABO blood group antigens was known. From January 2000 to October 2007, 122 patients with known blood groups and the diagnosis of OHSS were hospitalized. OHSS classification, pregnancies, age and time of in-patient treatment were collated. Two control groups were established. One group comprised 177 patients treated for infertility without developing OHSS (treatment/no OHSS) and known blood groups. A second one consisted of 2289 obstetric and gynaecological patients (O/G). OHSS grade I, II or III was found in 20, 47 and 55 patients, respectively. The pregnancy rate was 50.8% and did not differ among the different OHSS grades. Blood group A was significantly more frequent and blood group O less frequent in patients with early-onset OHSS compared with the two control cohorts (P = 0.009 versus treatment/no OHSS; P = 0.001 versus O/G). The odds ratio for patients with blood group A versus O to develop early-onset OHSS was 2.169 and 2.262, respectively. No increased risk for late-onset OHSS was found. Blood group A may be associated with early-onset OHSS in Caucasians.

Association of FSH receptor and CYP19A1 gene variations with sterility and ovarian hyperstimulation syndrome.

Severe ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening complication during assisted reproduction technology (ART). The aetiology of this condition is still not fully understood. Several gene variations in the FSH receptor (FSHR) gene have been identified for the very rare cases of spontaneous OHSS. There are only few published data on gene variations in sterility and iatrogenic OHSS and no data regarding aromatase (cytochrome P450 19A1; CYP19A1). Ninety-one ART patients with OHSS, eighty-eight ART patients without OHSS and ninety-seven women with assumed normal fecundity were analysed for the FSHR single nucleotide polymorphism (SNP) gene variations Asn680Ser (rs6166), Ala189Val, Ile160Thr, Thr449Ile (rs28928870) and the CYP19A1 rs10046 locus using real-time PCR. In addition, exon 10 of FSHR of two patients with spontaneous hyperreactio luteinalis (HL) was sequenced. Significantly lower frequencies of homozygous Ser680/Ser680 (P=0.035) and heterozygous Thr160/Ile160 (P=0.039) were found in patients with normal fecundity than those undergoing ART. The Ile160Thr SNP with a frequency of 6.7 and 6.1% in ART patients with and without OHSS respectively does not represent a rare mutation as previously published. There were no differences in the frequencies of all other gene variations. Of two patients with HL, both had homozygous point mutations for Ser680/Ser680 and one was heterozygous for Ile160Thr and CYP19A1 rs10046. The FSHR gene variations Asn680Ser as well as Ile160Thr may be contributing factors in unexplained sterility. The other FSHR coding gene variations and CYP19A1 rs10046 investigated are most likely not involved in the aetiology of iatrogenic OHSS or sterility.

First retransplantation of cryopreserved ovarian tissue following cancer therapy in Germany.

INTRODUCTION: New anticancer treatments have increased survival rates for cancer patients but often at the cost of sterility. One way of preserving fertility in these patients is the use of cryopreservation of ovarian tissue with subsequent retransplantation following a period of recurrence-free survival. We report the follow-up of the first case of retransplantation of ovarian tissue in Germany. METHODS: Immediately following the diagnosis of anal cancer, ovarian tissue was removed laparoscopically, and cryopreserved. The patient was then treated with combined radiochemotherapy, which resulted in iatrogenic premature ovarian failure, and was associated with inhibin B serum levels lower than 10 ng/L. After the 2.5 year period of cancer remission, the cryopreserved ovarian tissue was retransplanted orthotopically. RESULTS: Five months later estradiol serum levels had risen from lower than 20 pg/mL to 436 pg/mL. Three ovarian follicles were detected ultrasonographically in the pelvic side wall. Finally the patient reported her first menstruation after the intervention. The endocrine activity of the transplanted cryopreserved tissue has demonstrated viability, and the ability to develop. DISCUSSION: Cycle monitoring and timed intercourse should now help to achieve conception. These first results from Germany for retransplantation of cryopreserved ovarian tissue clearly show its potential for preserving fertility.

Update on ovarian hyperstimulation syndrome: Part 1--Incidence and pathogenesis.

Ovarian hyperstimulation syndrome (OHSS) is a rare and potentially life-threatening complication during controlled ovarian stimulation. It can be associated with severe morbidity and may even be fatal. The etiology of the condition and predisposing factors are still not fully understood. Data concerning pathophysiology in patients with OHSS were searched using PubMed and other medical data bases. The incidence of severe OHSS, as calculated by World Health Organization (WHO), is 0.2-1% of all stimulation cycles in assisted reproduction. Considerations on OHSS classifications and forms of manifestations are discussed in detail. New insights concerning genetics and altered FSH receptor are given. OHSS may involve, according to its grade of severity, elevated or decreased levels of growth factors, cytokines, mediators, changes in hormones, renin-angiotensin and kinin-kallikrein system. There are massive electrolytic imbalances and changes in hemodynamic and fluid metabolism. Furthermore, liver and pulmonary dysfunction is observed as well as increased coagulation with subsequent thromboembolism. The influence of OHSS on the pregnancy rate and outcome of pregnancy is a matter of controversy. Patients with OHSS have high pregnancy rates with a tendency to an increased incidence of abortion.

Low sex hormone-binding globulin as a predictive marker for insulin resistance in women with hyperandrogenic syndrome.

BACKGROUND: The aim of the present study is to assess insulin resistance (IR) in women with hyperandrogenic syndrome, which was suggested to replace the term polycystic ovary syndrome by the Androgen Excess Society, and to evaluate whether sex hormone-binding globulin (SHBG) can be used as a predictive marker of IR in hyperandrogenic women. METHODS: Clinical, metabolic, and endocrine parameters were measured, and an oral glucose tolerance test was carried out. The women were classified as IR group or non-IR group, in accordance with defined cutoff points for the homeostatic model assessment of IR (HOMA-IR) at > or =2.5, the quantitative insulin sensitivity check index at < or = 0.33, and the Matsuda insulin sensitivity index (ISI) at < or = 5. RESULTS: The women classified as having IR had a significantly higher body mass index (BMI) and free androgen index (FAI) and showed significantly lower SHBG and high-density lipoprotein (HDL) levels, regardless of the indices used. However, with the Matsuda ISI, generally more women were diagnosed as having IR, and this group had significantly higher total testosterone and triglyceride values, as well as a higher incidence of hirsutism. CONCLUSIONS: Women who were classified as being insulin resistant using insulin sensitivity indices showed significantly higher BMI and FAI values and lower SHBG and HDL levels. However, the Matsuda ISI may be more favorable for identifying IR in hyperandrogenic women. SHBG may serve as a predictive marker of IR in these women, particularly in those who are obese.

Severe ovarian hyperstimulation syndrome in a twin pregnancy after intracytoplasmic sperm injection.

A 35-year-old woman developed bilateral jugular thrombosis in the seventh gestational week in a twin pregnancy after severe ovarian hyperstimulation syndrome (OHSS) and intracytoplasmic sperm injection (ICSI). Due to progressive thrombosis and further complications despite anticoagulation therapy, the pregnancy was terminated in the ninth gestational week. Thromboembolic events are a serious complication associated with OHSS after assisted reproduction techniques. In these cases, a pregnancy can usually be protected by administering anticoagulation therapy, but our case shows that there may be exceptions to this. Screening for thrombophilia should be considered in patients who are at risk for OHSS and deep vein thrombosis.

Tubal transport of spermatozoa does not appear to be dependent on normal cilia function.

OBJECTIVE: To report the case of a woman with Kartagener's syndrome with complete immotility of ciliae and normal transport of spermatozoa. DESIGN: Case report. PATIENTS: A 31-year-old woman with Kartagener's syndrome. SETTING: Medical university-affiliated teaching hospital. INTERVENTION(S): Ultrasonography, hysterosalpingoscintigraphy using technetium-99m-labeled macroaggregates of human serum albumin, application of oxytocin. MAIN OUTCOME MEASURE(S): Dynamic anteroposterior scintigraphy using a gamma camera. RESULT(S): The transport of labeled macrospheres through the fallopian tube into the peritoneal cavity on the side of the leading follicle, compared to the contralateral oviduct where the labeled material may have accumulated within the fallopian tube, is similar to those reported in normal fertile women. CONCLUSION(S): Transport of spermatozoa is not dependent on normal ciliary function.

Long-term administration of testosterone undecanoate every 3 months for testosterone supplementation in female-to-male transsexuals.

CONTEXT: The most common treatment regimen in female-to-male transsexuals is administration of short-acting testosterone esters im every 2 wk. OBJECTIVE: Our objective was to report the effects of administering long-acting testosterone undecanoate every 3 months on hormonal and clinical changes, mortality, morbidity, and safety during the first year of treatment in female-to-male transsexuals. DESIGN: This was a 1-yr observational study. SETTING: The setting was an outpatient department at a university hospital. PATIENTS: A total of 35 female-to-male transsexuals completed the first year of observation, whereas two patients discontinued the treatment regimen due to serious hypertension. INTERVENTION: The intervention was 1-yr im treatment with long-acting testosterone undecanoate every 3 months. MAIN OUTCOME MEASURES: Gonadotropins, steroid hormones, liver enzymes, lipids, blood and coagulation parameter, body mass index, blood pressure, bone mineral density, and endometrium thickness were measured at the beginning of cross-sex hormone treatment and after 12 months. The mortality, morbidity, adverse effects, and desired clinical changes were recorded. RESULTS: There was a significant decrease in LH, prolactin, SHBG, high-density lipoprotein levels, and endometrium thickness, and a significant increase in body mass index, systolic and diastolic blood pressure, total testosterone and calculated androgens, triglycerides, hemoglobin, and hematocrit levels. No mortality was observed. Two cases of hypertension were noted. The patients reported a desirable increase in libido and clitoral growth. Acne was observed in five patients (14.3%). CONCLUSIONS: The treatment of female-to-male transsexuals with long-acting testosterone undecanoate may be a feasible and safe option for testosterone augmentation in these subjects. However, monitoring of blood pressure should not be ignored during the treatment, to identify patients liable to develop hypertension.

The effect of a GnRH agonist on cryopreserved human ovarian grafts in severe combined immunodeficient mice.

This prospective study compares the effect of a GnRH agonist on the number of follicles in different developmental stages in cryopreserved human ovarian grafts transplanted into gonadotropin-stimulated or not stimulated severe combined immunodeficient mice (SCID mice). Human ovarian tissue from seven patients was cryopreserved with an open-freezing system and xenotransplanted in SCID mice. The SCID mice were then treated according to different stimulation protocols. The survival of the tissue after cryopreservation was examined by LIVE/DEAD viability staining or transplanted in the neck muscle of 41 SCID mice. Development of follicles, estradiol production, vaginal cytology, and uterus weight were assessed after 15 weeks with or without gonadotropin stimulation. Viable follicles were detected in all frozen/thawed specimens using the LIVE/DEAD assay. Triptorelin, a GnRH agonist, caused a significant reduction of follicles in all developmental stages in the non-gonadotropin-stimulated animals (P<0.001). In gonadotropin-stimulated animals, GnRH agonist treatment has no significant effect on primordial, primary and preantral follicle count, whereas the antral follicles were significantly fewer (P = 0.03). The GnRH agonist treatment is not able to prevent the primordial follicle depletion after the xenografting of ovarian tissue in SCID mice with or without gonadotropin stimulation. Furthermore, it causes an additional loss of follicles if administered during the critical neovascularization period after the transplantation.

Endocrinological markers for assessment of hyperandrogenemia in hirsute women.

BACKGROUND: Measured endocrinological parameters (total testosterone [TT], free testosterone [FT], dihydrotestosterone [DHT], dehydroepiandrosterone sulfate [DHEAS], and sex hormone binding globulin [SHBG]) and calculated parameters (calculated FT (cFT), calculated bioavailable testosterone (cBT), and the free androgen index [FAI]) in women with hirsutism were compared to the values of a control group. The question remains if cFT or cBT are more appropriate markers for assessment of hyperandrogenemia in clinical situations such as hirsutism in women. METHODS: Sixty-six women showed an modified Ferriman-Gallwey (mF-G) score of >or=6 and were classified as hirsutism group and 58 women showed mF-G scores of

Update on ovarian hyperstimulation syndrome: part 2--clinical signs and treatment.

Patients with polycystic ovary syndrome (PCOS), hyperandrogenemia and hypothalamic ovarian dysfunction have a predisposition for developing ovarian hyperstimulation syndrome (OHSS). Choosing treatment protocols carefully, cautious stimulation, minimizing hCG dosages for ovulation induction, and refraining from embryo transfer in case of doubt, can markedly reduce the risk. In the treatment of moderate and severe hyperstimulation syndrome, adequate hydration with fluid balance, prophylaxis against thrombosis, ascites drainage when appropriate, and close monitoring and intensive-care monitoring if necessary, must be ensured. The aim of procedures in reproductive-medicine should be to achieve pregnancy rates that are as high as possible with as few side effects of the treatment as possible.

Course of ovarian hyperstimulation syndrome in 19 intact twin pregnancies after assisted reproduction techniques, with a case report of severe thromboembolism.

Ovarian hyperstimulation syndrome (OHSS) is a serious complication of assisted reproduction techniques using in vitro fertilization and intracytoplasmic sperm injection (IVF/ICSI). Its etiology has still not yet been fully resolved. Human chorionic gonadotrophin, administered exogenously as well as produced endogenously during pregnancy, is responsible for the onset of OHSS, and high levels of estradiol appear to worsen the condition. In this case series, the course of mild to severe OHSS was evaluated in 19 intact twin pregnancies after IVF/ICSI. Another serious complication associated with OHSS is thromboembolic events. In these cases, the pregnancy can be protected through anticoagulation treatment, but there may be exceptions to this. This series includes a case of bilateral thrombosis of the internal and external jugular veins in the 7th gestational week in a twin pregnancy after OHSS and ICSI, with termination of the pregnancy in the 9th gestational week due to progressive thrombosis during anticoagulation therapy.

Perfused non-pregnant swine uteri: a model for evaluating transport mechanisms to the side bearing the dominant follicle in humans.

Adequate uterine contractility and periovulatory peristalsis, interpreted as "rapid sperm transport" to the side bearing the dominant follicle, may be a precondition for successful reproduction in humans. Estrogen and progesterone fluctuate characteristically during the menstrual cycle, and their source is the dominant follicle and corpus luteum. The question is, how is the direction to the left or right side of transport mechanisms influenced? An extracorporeal perfusion model of the swine uterus was used that maintained the uterus in a functional condition and that was suitable for the study of physiological questions. The effects of side-dependent estrogen, progesterone, and estrogen plus progesterone perfusion on oxytocin-induced uterine peristalsis were assessed using two intrauterine microcatheters placed in each horn of the swine uterus. Estrogen perfusion was associated with an increase in intrauterine pressure (IUP) in a dose-dependent manner only in the estrogen-perfused horn of the swine uterus. There was a significant difference between the IUP increase measured in the estrogen-perfused horn and that in the non estrogen-perfused horn of the swine uterus. Progesterone perfusion showed no effect in general. Furthermore, progesterone antagonized the estrogen effects. This study demonstrates that side-dependent estrogen perfusion resulted in side-dependent contractility in the swine uterus perfusion system used. These observations show that estrogen stimulates uterine contractility in the estrogen-perfused uterine horn and that estrogens may be the "trigger" for the transport mechanisms to the side bearing the dominant follicle during the periovulatory phase through their locally increased concentration and distribution via the utero-ovarian counter-current system in humans.