BackgroundMüllerian aplasia (MA) is a congenital disorder of the female reproductive tract with absence of uterus and vagina with paramount impact on a woman’s life. Despite intense research, no major genes have been found to explain the complex genetic etiology.Methods and ResultsWe have used several genetic methods to study 112 patients with MA. aCGH identified CNVs in 8/50 patients (16%), including 16p11.2 and 17q12 deletions previously associated with MA. Subsequently, another four patients were shown to carry the ~0.53 Mb deletion in 16p11.2. More importantly, sequencing of TBX6, residing within 16p11.2, revealed two patients carrying a splice site mutation. Two previously reported TBX6 variants in exon 4 and 6 were shown to have a significantly higher frequency in patients (8% and 5%, respectively) than in controls (2% each). We also sequenced LHX1 and found three apparently pathogenic missense variants in 5/112 patients. Altogether, we identified either CNVs or variations in TBX6 or LHX1 in 30/112 (26.8%) MA patients. CNVs were found in 12/112 (10.7%), patients, novel variants in TBX6 or LHX1 in 7/112 (6.3%), and rare variants in TBX6 in 15/112 (13.4%) patients. Furthermore, four of our patients (4/112, 3.6%) were shown to carry variants in both TBX6 and LHX1 or a CNV in combination with TBX6 variants lending support to the complex genetic etiology of MA.ConclusionsWe have identified TBX6 as a new gene associated with MA. Our results also support the relevance of LHX1 and CNVs in the development of this congenital malformation.

IntroductionThe aim of this study is to report the current status of ovarian tissue cryopreservation among alternatives for fertility preservation in the Nordic countries.Material and methodsA questionnaire was sent to 14 Nordic academic reproductive centers with established fertility preservation programs. It covered fertility preservation cases performed up to December 2014, standard procedures for ovarian tissue cryopreservation and oocyte cryopreservation and reproductive outcomes following ovarian tissue transplantation.ResultsAmong the Nordic countries, Denmark and Norway practice ovarian tissue cryopreservation as a clinical treatment (822 and 164 cases, respectively) and their programs are centralized. In Sweden (457 cases), ovarian tissue cryopreservation is practiced at five of six centers and in Finland at all five centers (145 cases). Nearly all considered ovarian tissue cryopreservation to be experimental. In Iceland, embryo cryopreservation is the only option for fertility preservation. Most centers use slow‐freezing methods for ovarian tissue cryopreservation. Most patients selected for ovarian tissue cryopreservation were newly diagnosed with cancer and the tissue was predominantly retrieved laparoscopically by unilateral oophorectomy. Only minor complications were reported. In total, 46 women have undergone ovarian tissue transplantation aiming at recovering fertility, 17 healthy children have been born and several additional pregnancies are currently ongoing. Whenever patients’ clinical condition is permissive, oocyte cryopreservation after hormonal stimulation is preferred for fertility preservation. Between 2012 and 2014, a smaller proportion of females have undergone fertility preservation in the Nordic centers, in comparison to males (1:3).ConclusionsOverall, ovarian tissue cryopreservation was reported to be safe. Slow freezing methods are still preferred. Promising results of recovery of fertility have been reported in Nordic countries that have initiated ovarian tissue transplantation procedures.

The main aim of this retrospective study was to evaluate the occurrence of hypothyroidism among Finnish women with infertility. For this purpose, the records of 335 women presenting for the first time with infertility at the outpatient clinic of reproductive endocrinology at Turku University Central Hospital during a 3-year period (January 1992 to December 1994) were reviewed. Due to missing data, 36 women were excluded from the analysis. Thyroid function was screened by measuring serum thyroid stimulating hormone (TSH) levels in conjunction with serum prolactin using immunoradiometric assays. Prior to enrolment in the infertility examinations, ten out of 299 women had used thyroxine substitution for primary hypothyroidism. In the TSH screening test, 12 women (4%) exhibited elevated serum TSH levels ranging from 5.7 to 32 mU/l. Three of these cases were previously diagnosed with hypothyroidism and were using an inadequate dose of thyroxine. The prevalence of abnormal TSH levels was highest in the ovulatory dysfunction (6.3%) and unknown infertility (4.8%) groups and lowest in the tubal infertility (2.6%) and male infertility (1.5%) groups, although no statistically significant differences between the groups were observed. Oligo/amenorrhea was present in 101 (34%) women in the whole study population and in eight (67%, p < 0.5) women with elevated serum TSH at screening. The relatively high occurrence of abnormal TSH levels in infertile women with ovulatory dysfunctions or unknown infertility, as well as with oligo/amenorrhea, emphasizes the importance of TSH screening in these patient groups.

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During the secretory phase of the menstrual cycle, the composition of extracellular matrix (ECM) in endometrium changes to favour implantation. In the present study, we have analysed whether some cases of unexplained infertility and recurrent abortions could be explained by abnormal production or turnover of endometrial ECM. Comparison of mRNA levels of a panel of collagens, matrix metalloproteinases (MMP), tissue inhibitors of metalloproteinases (TIMP) and cathepsins in the samples revealed higher levels of type I collagen, MMP-2 and cathepsin H and decreased levels of TIMP-3 mRNA in mid-secretory endometrium of patients with unexplained infertility and/or recurrent miscarriages when compared with normal mid-secretory endometrium. Furthermore, changes were also seen in the levels of type I collagen and TIMP-3 mRNA between the proliferative and mid-secretory phases of normal endometrium. The results suggest an altered ECM turnover in the endometrium of patients with fertility disorders prior to implantation.