Adrenarche and pubarche in girls with turner syndrome during growth-promoting therapy with human growth hormone.

BACKGROUND: Data on adrenarche and pubarche in girls with Turner syndrome (TS) are inconsistent in the literature. METHODS: The cohort consisted of 94 girls and young women with TS born between 1971 and 2001 (age range: 3.1-23.2 yrs.), who were treated with human growth hormone and regularly presented at our outpatient clinic every 4 to 6 months.The longitudinal data of all patients were ascertained retrospectively from patient charts. The data collection ended in January 2016. Adrenarche was assessed by serum DHEAS levels and pubertal status by Tanner stages. Pubarche was defined as the appearance of pubic hair (PH2), whereas spontaneous puberty was defined as Tanner stage B2. The patients were retrospectively subdivided in two groups with regard to pubertal development: group 1 (n = 21) with spontaneous puberty and group 2 (n = 70) with induced puberty. Since blood samples were not taken at every visit, we generated seven groups according to the age of the children at which the blood samples were taken: 3-5, 5-7, 7-9, 9-11, 11-13, 13-15, and 15-17 yrs. Serum DHEAS and follicle-stimulating hormone (FSH) levels were measured by chemiluminescence immunoassay and compared with those of a control group of healthy girls. RESULTS: Adrenarche started in TS girls between 5 and 7 years. TS girls had higher DHEAS levels than the control group, with statistically significant differences in the age groups 7 to 17 years. No differences were determined between the TS girls with spontaneous puberty and those with POI. TS girls in group 2 reached the Tanner stages PH2 (p < 0.04), PH3 (p < 0.01), PH4 and PH5 (p < 0.001) markedly later than TS girls in group 1. CONCLUSIONS: The onset of adrenarche in girls with TS undergoing GH therapy does not differ from that in healthy girls. However, adrenarche is more pronounced in girls with TS. There is no difference in DHEAS levels between the TS girls with spontaneous puberty and the TS girls with primary ovarian insufficiency (POI), while the tempo of pubarche is markedly slower in the girls with POI.

Retraction Note: Improving usability and pregnancy rates of a fertility monitor by an additional mobile application: results of a retrospective efficacy study of Daysy and DaysyView app.

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Miscarriages in families with an offspring that have classic congenital adrenal hyperplasia and 21-hydroxylase deficiency.

BACKGROUND: The most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency (CAH). Both men and women with classic CAH have lower fertility rates than the general population, and an increased rate of miscarriages has been reported in affected women. There are no data on the incidence rate of miscarriages in families with an offspring that have classic CAH. METHODS: We studied families with a history of classic CAH. The families came from different parts of Germany and attended the annual meeting of the German CAH support group for parents and patients which was held in Hamburg in September 2014. The data was collected anonymously by a paper-based questionnaire which was completed by the families at home. The families also accepted the responsibility to address this question to their siblings. In all, the data of 50 families with at least one child with classic CAH, and the data of 164 parental siblings were available for evaluation. Miscarriage rates were calculated in relation to the reported pregnancies. RESULTS: Twenty-two miscarriages were reported from 19 families. At least one miscarriage occurred in 38% of the families, three families experienced two miscarriages and 16 families had one miscarriage each. The mean miscarriage rate was 15.8%. The heterozygous mothers had a total of 90 siblings (41 m, 49 f), while 74 siblings (33 m, 41 f) were reported from the heterozygous fathers. The miscarriage rate was 10.1% in the families of the mothers` siblings, and 11.4% in the families of the fathers` siblings. The genotype was known in all parents that have an offspring with classic CAH, but not defined in 82% of the maternal siblings, and in 86% of the paternal siblings. No child with classic CAH has been diagnosed in any of the sibling's families to date. CONCLUSION: Our data show that the miscarriage rate in German families with a child with classic CAH is not elevated.

Comparison of dienogest and progesterone effects on uterine contractility in the extracorporeal perfusion model of swine uteri.

INTRODUCTION: Endometriosis is associated with hyperperistalsis and dysperistalsis in the uterus, and it has been shown that progesterone leads to a decrease in uterine contractility. The synthetic gestagen dienogest is often administered in women who are receiving conservative treatment for endometriosis, and it may be the treatment of choice. The present study investigated the effects of dienogest on uterine contractility in comparison with the known inhibitory effect of progesterone. MATERIAL AND METHODS: Eighty swine uteri were examined using an established extracorporeal perfusion model. The uteri were perfused for at least 4 hours with progesterone, dienogest, or a modified Krebs-Ringer solution as the control group, with uterine contractions being measured using an intrauterine microchip catheter. The amplitude and frequency of contractions and the area under the curve (AUC), reflecting overall contractility, were measured at two separate locations (the isthmus and fundus). RESULTS: Progesterone led to a significant decrease in the amplitude of uterine contractions and to reduced overall pressure (AUC) at the isthmus and fundus. Dienogest led to a significant decrease in the amplitude of contractions and overall pressure (AUC) in the area of the isthmus, but the decrease near the fundus was not significant. The frequency of uterine contractions was not influenced by either progesterone or dienogest. CONCLUSIONS: These results confirm the known inhibitory effect of progesterone on uterine contractility (relative to amplitude of contractions and overall contractility), affecting the whole organ. Perfusion of the uterus with dienogest also led to a general decrease in uterine contractility similar to the effect of progesterone.

Improving usability and pregnancy rates of a fertility monitor by an additional mobile application: results of a retrospective efficacy study of Daysy and DaysyView app.

BACKGROUND: Daysy is a fertility monitor that uses the fertility awareness method by tracking and analyzing the individual menstrual cycle. In addition, Daysy can be connected to the application DaysyView to transfer stored personal data from Daysy to a smartphone or tablet (IOS, Android). This combination is interesting because as it is shown in various studies, the use of apps is increasing patients´ focus on their disease or their health behavior. The aim of this study was to investigate if by the additional use of an App and thereby improved usability of the medical device, it is possible to enhance the typical-use related as well as the method-related pregnancy rates. RESULT: In the resultant group of 125 women (2076 cycles in total), 2 women indicated that they had been unintentionally pregnant during the use of the device, giving a typical-use related Pearl-Index of 1.3. Counting only the pregnancies which occurred as a result of unprotected intercourse during the infertile (green) phase, we found 1 pregnancy, giving a method-related Pearl-Index of 0.6. Calculating the pregnancy rate resulting from continuous use and unprotected intercourse exclusively on green days, gives a perfect-use Pearl-Index of 0.8. CONCLUSION: It seems that combining a specific biosensor-embedded device (Daysy), which gives the method a very high repeatable accuracy, and a mobile application (DaysyView) which leads to higher user engagement, results in higher overall usability of the method.

Hyperandrogenemia and high prolactin in congenital utero-vaginal aplasia patients.

Patients with the Mayer-Rokitansky-Küster-Hauser syndrome (MRKH) have a congenital utero-vaginal cervical aplasia, but normal or hypoplastic adnexa and develop with normal female phenotype. Some reports mostly demonstrated regular steroid hormone levels in small MRKH cohorts including single MRKH patients with hyperandrogenemia and a clinical presentationof hirsutism and acne has also been shown. Genetically a correlation of WNT4 mutations with singular MRKH patients and hyperandrogenemia was noted. This study analyzed the hormone status of 215 MRKH patients by determining the levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, 17-OH progesterone, testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG) and prolactin to determine the incidence of hyperandrogenemia and hyperprolactinemia in MRKH patients. Additional calculations and a ratio of free androgen index and biologically active testosterone revealed a hyperandrogenemia rate of 48.3%, hyperprolactinemia of 9.8% and combined hyperandrogenemia and hyperprolactinemia of 4.2% in MRKH patients. The rates of hirsutism, acne and especially polycystic ovary syndrome (PCOS) were in the normal range of the population and showed no correlation with hyperandrogenemia. A weekly hormone assessment over 30 days comparing 5 controls and 7 MRKH patients revealed high androgen and prolactin, but lower LH/FSH and SHBG levels with MRKH patients. The sequencing of WNT4, WNT5A, WNT7A and WNT9B demonstrated no significant mutations correlating with hyperandrogenemia. Taken together, this study shows that over 52% of MRKH patients have hyperandrogenemia without clinical presentation and 14% hyperprolactinemia, which appeals for general hormone assessment and adjustments of MRKH patients.

What do patients want to know about contraception and which method would they prefer?

PURPOSE: The aim of this study was to determine the extent to which women's choice of contraceptive method depends on the advice received from their gynecologist and whether more intensive counseling might lead to more frequent use of long-acting reversible contraception (LARC). METHODS: A total of 1089 physicians and 18,521 women responded to 32 or 37 questions, respectively, using an online questionnaire. The women were asked about their current use of contraceptive methods, the extent of their satisfaction with them, their satisfaction with the counseling they had received, and whether they wanted to have more information about contraception. The physicians were similarly asked which contraceptive methods were being used, how satisfied with them they were, how they would assess their patients' satisfaction with them, and whether the women wanted to have more information. RESULT: The results showed that 61% of the women were using oral contraceptives, and a total of only 9% were using behavior-independent long-term contraceptive methods. However, 60% of the women stated that long-term contraception would be an option for them if they had more information about it. Gynecologists underestimated this figure, at only 18%. Whereas 66% of the gynecologists believed that their patients never forgot to take the pill, nearly, half of the women stated that they had forgotten it at least once during the previous 3 months. CONCLUSION: The small number of women who use long-term contraception is in clear contrast to the fact that many women want to have a very safe but also behavior-independent method.

Operative techniques and complications of extraction and transplantation of ovarian tissue: the Erlangen experience.

PURPOSE: Extracting ovarian tissue before oncologic therapy and transplanting it afterwards are increasingly being used to preserve fertility in women. This study describes standardized and safe operative procedures, with few complications, and reports the resulting ovarian function and pregnancy rates. METHODS: The standardized operative techniques for removing and transplanting ovarian tissue used at the Erlangen center are: for tissue removal, one-third to half of the tissue from one ovary is excised with scissors, without tissue coagulation; for subsequent transplantation, pieces of ovarian tissue are placed in a retroperitoneal pocket without closure of the pocket. RESULTS: Between January 2007 and December 2015, ovarian tissue was extracted in 399 women and transplanted following cancer therapy in 38. No surgical complications were observed within 28 days. To date, there have been ten pregnancies and nine live births after transplantation in seven different women; 26 of the 38 women developed hormonal activity, confirmed by a menstrual cycle or raised serum estradiol levels. CONCLUSIONS: The techniques for laparoscopic removal and transplantation of ovarian tissue described here provide a standardized method with a very low risk of complications. The pregnancy rate after ovarian tissue transplantation, currently 15-30%, can be expected to rise further in the near future.

Can Classifications Adequately Represent Genital Malformations?: EVA Study ( E SHRE/ESGE | V CUAM | A FS) - A Prospective Multicenter Study to Evaluate the Current Female Genital Malformation Classifications.

Introduction Genital malformations are a common clinical occurrence that can be represented using different classifications. Reproducibility is an essential quality characteristic for a classification, and it plays an important role, especially in consultations and the treatment of infertile patients and in obstetric management. The aim of this study is to demonstrate the reproducibility and clinical practicality of three commonly used classifications: the ESHRE/ESGE (European Society of Human Reproduction and Embryology/ European Society for Gynecological Endoscopy), VCUAM (Vagina Cervix Uterus Adnex-associated Malformation), and AFS (American Fertility Society) classifications. Materials and Methods Sixty-five patients with female genital malformations were included in this prospective, multicenter, exploratory, observational study. All participants underwent a clinical examination and a medical interview. The investigators were instructed to classify the presenting malformations according to the ESHRE/ESGE, VCUAM, and AFS classifications using a structured questionnaire. Investigators were asked whether the malformation could be reproducibly classified (yes/no) and about the grade (grade 1-5 from "very good" to "deficient") they would assign to each classification. Classification assessment was queried for vagina, cervix, uterus, adnexa, and associated malformations and was scored from 1 to 5. Results Reproducibility was rated as 80% (n = 52/65), 92.3% (n = 60/65), and 56.9% (n = 37/65) for the ESHRE/ESGE, VCUAM, and AFS classification, respectively. ESHRE/ESGE, VCUAM and AFS were rated as "very good" or "good" for 83.3%, 89.2%, and 10.8% of vaginal malformations; for 75.8%, 87.5%, and 24.2% of cervical malformations; and for 89.7%, 89.5%, and 86.2% of uterine malformations, respectively. VCUAM was rated as "very good" or "good" for 77.8% and 69.6% of adnexal malformations and associated malformations, respectively. ESHRE/ESGE and AFS were rated as "sufficient" or "deficient" for 100% and 75% of adnexal malformations and for 77.3% and 69.6% of associated malformations, respectively. Conclusion The prospective multicenter EVA ( E SHRE/ESGE | V CUAM | A FS) study revealed that the organ-based ESHRE/ESGE and VCUAM classifications of female genital malformations perform better in terms of reproducibility as well as in the assessment of individual compartments than the non-organ-based AFS classification.

Malformations in a cohort of 284 women with Mayer-Rokitansky-Küster-Hauser syndrome (MRKH).

BACKGROUND: The aim of this retrospective study was to describe the spectrum of genital and associated malformations in women with Mayer-Rokitansky-Küster-Hauser syndrome using evaluated diagnostic procedures and the Vagina Cervix Uterus Adnex - associated Malformation classification system (VCUAM). METHODS: 290 women with MRKH syndrome were clinically evaluated with using clinical examinations, abdominal and perineal/rectal ultrasound, MRI, and laparoscopy. RESULTS: Classification of female genital malformation according to the Vagina Cervix Uterus Adnex - associated Malformation classification system was possible in 284 women (97.9%). Complete atresia of Vagina (V5b) and bilateral atresia of Cervix (C2b) were found in 284 patients (100%). Uterus: bilateral rudimentary or a plastic uterine horns were found in 239 women (84.2%). Adnexa: normal Adnexa were found in 248 women (87.3%). Malformations: associated malformations were found in 126 of 282 evaluable women (44.7%), 84 women (29.6%) had malformations of the renal system. Of 284 women with Mayer-Rokitansky-Küster-Hauser syndrome 212 women (74.7%) could be classified as V5bC2bU4bA0. The most frequent classification was V5bC2bU4bA0M0 (46.8%) diagnosed in 133 of 284 women. CONCLUSIONS: Complete atresia of vagina and cervix were found in all patients, variable malformations were found with uterus and adnexa. A variety of associated malformations were present, predominantly of the renal system. It is therefore recommended that all patients with genital malformations should be evaluated for renal abnormalities.

High incidence of recurrent copy number variants in patients with isolated and syndromic Müllerian aplasia.

BACKGROUND: Congenital malformations involving the Müllerian ducts are observed in around 5% of infertile women. Complete aplasia of the uterus, cervix, and upper vagina, also termed Müllerian aplasia or Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, occurs with an incidence of around 1 in 4500 female births, and occurs in both isolated and syndromic forms. Previous reports have suggested that a proportion of cases, especially syndromic cases, are caused by variation in copy number at different genomic loci. METHODS: In order to obtain an overview of the contribution of copy number variation to both isolated and syndromic forms of Müllerian aplasia, copy number assays were performed in a series of 63 cases, of which 25 were syndromic and 38 isolated. RESULTS: A high incidence (9/63, 14%) of recurrent copy number variants in this cohort is reported here. These comprised four cases of microdeletion at 16p11.2, an autism susceptibility locus not previously associated with Müllerian aplasia, four cases of microdeletion at 17q12, and one case of a distal 22q11.2 microdeletion. Microdeletions at 16p11.2 and 17q12 were found in 4/38 (10.5%) cases with isolated Müllerian aplasia, and at 16p11.2, 17q12 and 22q11.2 (distal) in 5/25 cases (20%) with syndromic Müllerian aplasia. CONCLUSION: The finding of microdeletion at 16p11.2 in 2/38 (5%) of isolated and 2/25 (8%) of syndromic cases suggests a significant contribution of this copy number variant alone to the pathogenesis of Müllerian aplasia. Overall, the high incidence of recurrent copy number variants in all forms of Müllerian aplasia has implications for the understanding of the aetiopathogenesis of the condition, and for genetic counselling in families affected by it.

Oral Progestins in Hormonal Contraception: Importance and Future Perspectives of a New Progestin Only-Pill Containing 4 mg Drospirenone.

Hormonal contraceptives are an effective and safe method for preventing pregnancy. Progestins used in contraception are either components of combined hormonal contraceptives (tablets, patches or vaginal rings) or are used as a single active ingredient in progestin mono-preparations (the progestin-only pill (POP), implants, intrauterine systems or depot preparations). Progestins are highly effective in long-term contraception when used properly, and have a very good safety profile with very few contraindications. A new oestrogen-free ovulation inhibitor (POP) has recently been authorised in the USA and the EU. This progestin mono-preparation contains 4 mg of drospirenone (DRSP), which has anti-gonadotropic, anti-mineralocorticoidic and anti-androgenic properties. The hormone administration regimen of 24 days followed by a 4-day hormone-free period was chosen to improve bleeding control and to maintain oestradiol concentrations at early follicular-phase levels, preventing oestrogen deficiency. Clinical trials have demonstrated a high contraceptive effectiveness, a very low risk of cardiovascular side effects and a favourable menstrual bleeding pattern. Due to the long half-life of DRSP (30 - 34 hours), the effectiveness of the preparation is maintained even if a woman forgets to take a pill on a single occasion. Studies involving deliberate 24-hour delays in taking a pill have demonstrated that ovulation inhibition is maintained if a single pill is missed. Following a summary of the current status of oestrogen-free contraception, this review article will describe the clinical development programme of the 4 mg DRSP mono-preparation and the resulting data on the effectiveness and safety of this new oestrogen-free oral hormonal contraceptive.

Correction: Oral Progestins in Hormonal Contraception: Importance and Future Perspectives of a New Progestin Only-Pill Containing 4 mg Drospirenone.

[This corrects the article DOI: 10.1055/a-1471-4408.][This corrects the article DOI: 10.1055/a-1471-4408.].

Hormonal Contraception. Guideline of the DGGG, OEGGG and SGGG (S3 Level, AWMF Registry Number 015/015, January 2020).

Aims This is an official interdisciplinary guideline published and coordinated by the German Society for Gynecology and Obstetrics (DGGG), the Austrian Society for Gynecology and Obstetrics (OEGGG) and the Swiss Society for Gynecology and Obstetrics (SGGG). The guideline was developed for use in German-speaking regions and is backed by numerous professional societies and organizations. The aim of this guideline is to provide an evidence- and consensus-based overview of the diagnostic approach and the management of hormonal contraception based on a systematic evaluation of the relevant literature. Methods To compile this S3-guideline, a systematic search for evidence was carried out in PubMed and the Cochrane Library to adapt existing guidelines and identify relevant reviews and meta-analyses. A structured evaluation of the evidence was subsequently carried out on behalf of the Guidelines Commission of the DGGG, and a structured consensus was achieved based on consensus conferences attended by representative members from the different specialist societies and professions. Recommendations Evidence-based recommendations about the advice given to women requesting contraception were compiled. The guideline particularly focuses on prescribing contraceptives which are appropriate to women's individual needs, take account of her personal circumstances, and have few or no side effects.

Effects of intramuscular testosterone undecanoate on body composition and bone mineral density in female-to-male transsexuals.

INTRODUCTION: The most common treatment regimen in female-to-male transsexuals is administration of short-acting testosterone esters intramuscularly every 2 weeks. AIM: The aim of this study was to evaluate the effect of long-acting intramuscular testosterone undecanoate on body composition and bone mineral density during cross-sex hormone therapy in female-to-male transsexuals. METHODS: Forty-five female-to-male transsexuals (FtMs) were treated with injections of testosterone undecanoate 1,000 mg intramuscularly every 12 weeks over 24 months. MAIN OUTCOME MEASURES: Body composition, bone mineral density, hormone parameters, and lipids were compared after 12 months and after 24 months with baseline values. Sonographic findings in the ovaries and endometrium, clinical and adverse effects during the study period were recorded. RESULTS: There was a significant increase in lean mass in the FtMs during the study period in comparison with baseline values, whereas no change in BMI, fat mass, and bone mineral density was observed. There was a significant decline in gonadotropins, estradiol, dehydroepiandrosterone sulphate, sex hormone-binding globulin, and high-density lipoprotein, while testosterone and triglyceride levels increased significantly after 12 and 24 months. Ovaries remained unchanged and no noticeable endometrial pathology was observed. No mortality or morbidity was observed during the study period. We observed a cessation of menstrual bleeding, an increase in clitoral growth, libido, body and beard hair growth, deepened voices and decline in breast size. There was a significant increase in hemoglobin, hematocrit, glutamic-pyruvic transaminase, gamma-glutamyl transferase, and an increase in systolic blood pressure during the study period. CONCLUSIONS: There was an increase in lean mass during the study period in FtMs treated with testosterone undecanoate. Transsexual patients should be monitored for adverse effects on lipid profiles, blood pressure, and erythrocytosis during intramuscular testosterone undecanoate therapy.

Situation of Adolescent Contraceptive Use in Germany.

Introduction Would adolescent girls in Germany choose a different method of contraception to the combined oral contraceptive if provided with the appropriate information? Is there a need for long-acting contraception among our adolescent girls? How satisfied are female patients with the information they receive at their respective gynaecology practices, and how much do the girls know about different methods of contraception? Materials and Methods In the study "Thinking About Needs in COntraception" (TANCO), not only female patients, but also their respective gynaecologists were surveyed online about current methods of contraception, their satisfaction with these methods, and also their level of knowledge concerning the individual methods of contraception, the situation related to advice about different contraceptive options and their general satisfaction with gynaecological care. This article presents the data from the subset of adolescent girls aged 14 to 19 years (n = 2699) out of the total of 18 521 women surveyed. Results The girls surveyed were familiar with at least the name of more than five different methods of contraception (average 5.3). The doctors assumed that the respondents would know only 4.2 different methods. When asked explicitly about how the individual methods of contraception work, clear deficits became evident. This applies not only to the entire population of respondents, but also the users of the respective contraceptive method. In addition, a strong interest in long-acting contraception emerged from the survey, particularly among young women. Discussion The data from the TANCO study reveal a clear discrepancy between the existing contraception almost exclusively in the form of the contraceptive pill and the contraceptive options considered by adolescent girls if they are thoroughly informed. The need for education into alternatives to the pill is high, as is the willingness to use such alternatives after receiving information - much higher than the figures suggested by the gynaecologists.

Fertility Preservation for Patients with Malignant Disease. Guideline of the DGGG, DGU and DGRM (S2k-Level, AWMF Registry No. 015/082, November 2017) - Recommendations and Statements for Girls and Women.

AIM: The aim of this official guideline published by the German Society of Gynecology and Obstetrics (DGGG) and coordinated with the German Society of Urology (DGU) and the German Society of Reproductive Medicine (DGRM) is to provide consensus-based recommendations, obtained by evaluating the relevant literature, on counseling and fertility preservation for prepubertal girls and boys as well as patients of reproductive age. Statements and recommendations for girls and women are presented below. Statements or recommendations for boys and men are not the focus of this guideline. METHODS: This S2k guideline was developed at the suggestion of the guideline commission of the DGGG, DGU and DGRM and represents the structured consensus of representative members from various professional associations (n = 40). RECOMMENDATIONS: The guideline provides recommendations on counseling and fertility preservation for women and girls which take account of the patient's personal circumstances, the planned oncologic therapy and the individual risk profile as well as the preferred approach for selected tumor entities.

Effects of interactions between progesterone and prostaglandin on uterine contractility in a perfused swine uterus model.

BACKGROUND/AIM: Uterine quiescence at the time of embryo transfer is a prerequisite for successful in vitro fertilization (IVF). This study assessed whether prostaglandin-induced contractions in the perfused swine uterus can be reduced by progesterone. MATERIALS AND METHODS: Fifty-eight non-pregnant swine uteri were perfused using an established extracorporeal perfusion model. Intrauterine pressure changes during perfusion with prostaglandin (PG) administration (PGE1, PGE2, PGF2α) and progesterone (1 pg/ml, 10 pg/ml, 25 pg/ml, 50 pg/ml) were assessed using an intrauterine double-chip microcatheter. RESULTS: The contraction-stimulating effect of PGs was clearly reduced by progesterone. Only PGE1 still triggered relevant contractions during continuous perfusion with progesterone solution, up to a concentration of 10 pg/ml. With PGE2 and PGF2α, a clear reduction of uterine contractility was observed even at at a progesterone concentration of 1 pg/ml. CONCLUSION: The extracorporal perfusion model of swine uteri shows that PG-induced contractions can be reduced in a dose-dependent manner by progesterone.

HOXA10 and HOXA13 sequence variations in human female genital malformations including congenital absence of the uterus and vagina.

Congenital genital malformations occurring in the female population are estimated to be 5 per 1000 and associate with infertility, abortion, stillbirth, preterm delivery and other organ abnormalities. Complete aplasia of the uterus, cervix and upper vagina (Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome) has an incidence of 1 per 4000 female live births. The molecular etiology of congenital genital malformations including MRKH is unknown up to date. The homeobox (HOX) genes HOXA10 and HOXA13 are involved in the development of human genitalia. In this investigation, HOXA10 and HOXA13 genes of 20 patients with the MRKH syndrome, 7 non-MRKH patients with genital malformations and 53 control women were sequenced to assess for DNA variations. A total of 14 DNA sequence variations (10 novel and 4 known) within exonic and untranslated regions were detected in HOXA10 and HOXA13 among our cohorts. Four HOXA10 and two HOXA13 DNA sequence variations were found solely in patients with genital malformations. In addition to mutations resulting in synonymous amino acid substitutions, in the HOXA10 gene a missense mutation was identified and predicted by computer analysis as probably damaging to protein function in two non-MRKH patients, one with a bicornate and the other patient with a septated uterus. A novel exonic HOXA10 cytosine deletion was also identified in a non-MRKH patient with a septate uterus and renal malformations resulting in a premature stop codon and loss of the homeodomain helix 3/4. This cytosine deletion and the missense mutation in HOXA10 were analysed by real time PCR and sequencing, respectively, in two additional larger cohorts of 103 patients with MRKH and 109 non-MRKH patients with genital malformations. No other patients were found with the cytosine deletion however one additional patient was identified regarding the missense mutation. Rare DNA sequence variations in the HOXA10 gene could contribute to the misdevelopment of female internal genitalia.