Non-classic cytochrome P450 oxidoreductase deficiency strongly linked with menstrual cycle disorders and female infertility as primary manifestations.

STUDY QUESTION: Can cytochrome P450 oxidoreductase deficiency (PORD) be revealed in adult women with menstrual disorders and/or infertility? SUMMARY ANSWER: PORD was biologically and genetically confirmed in five adult women with chronically elevated serum progesterone (P) who were referred for oligo-/amenorrhea and/or infertility. WHAT IS KNOWN ALREADY: PORD is an autosomal recessive disease typically diagnosed in neonates and children with ambiguous genitalia and/or skeletal abnormalities. It is responsible for the decreased activity of several P450 enzymes, including CYP21A2, CYP17A1 and CYP19A1, that are involved in adrenal and/or gonadal steroidogenesis. Little is known about the optimal way to investigate and treat patients with adult-onset PORD. STUDY DESIGN, SIZE, DURATION: In this series, we report five adult females who were evaluated in three tertiary endocrine reproductive departments between March 2015 and September 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Five women aged 19-38 years were referred for unexplained oligo-/amenorrhea and/or infertility. Genetic testing excluded 21-hydroxylase deficiency (21OH-D), initially suspected due to the increased 17-hydroxyprogesterone (17-OHP) levels. Extensive phenotyping, steroid profiling by mass spectrometry, pelvic imaging and next-generation sequencing of 84 genes involved in gonadal and adrenal disorders were performed in all patients. IVF followed by frozen embryo transfer (ET) under glucocorticoid suppression therapy was performed for two patients. MAIN RESULTS AND THE ROLE OF CHANCE: All patients had oligomenorrhea or amenorrhea. None had hyperandrogenism. Low-normal serum estradiol (E2) and testosterone levels contrasted with chronically increased serum P and 17-OHP levels, which further increased after adrenocorticotrophic hormone (ACTH) administration. Despite excessive P, 17OH-P and 21-deoxycortisol rise after ACTH stimulation suggesting non-classic 21OH-D, CYP21A2 sequencing did not support this hypothesis. Basal serum cortisol levels were low to normal, with inadequate response to ACTH in some women, suggesting partial adrenal insufficiency. All patients harbored rare biallelic POR mutations classified as pathogenic or likely pathogenic according to the American College of Medical Genetics and Genomics standards. Pelvic imaging revealed bilateral ovarian macrocysts in all women. IVF was performed for two women after retrieval of a normal oocyte number despite very low E2 levels during ovarian stimulation. Frozen ET under glucocorticoid suppression therapy led to successful pregnancies. LIMITATIONS, REASONS FOR CAUTION: The number of patients described here is limited and these data need to be confirmed on a larger number of women with non-classic PORD. WIDER IMPLICATIONS OF THE FINDINGS: The diagnosis of PORD must be considered in infertile women with chronically elevated P and 17OH-P levels and ovarian macrocysts. Differentiation of this entity from non-classic 21OH-D is important, as the multiple enzyme deficiency requires a specific management. Successful fertility induction is possible by IVF, providing that P levels be sufficiently suppressed by glucocorticoid therapy prior to implantation. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was used for this study. There are no potential conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Does prior hysteroscopy affect pregnancy outcome in primigravid infertile women?

OBJECTIVE: An increasing proportion of infertile women are subjected to hysteroscopy. The effect of hysteroscopy on the pregnancy rate in assisted reproduction has been demonstrated to be favorable, but cervical dilation in the course of hysteroscopy may have an adverse effect on pregnancy outcome. We sought to investigate the effect of hysteroscopy on the risk of early miscarriage, preterm delivery, low birthweight, and other complications of pregnancy. STUDY DESIGN: This was a longitudinal retrospective cohort study at a university hospital. Data of 654 first-time singleton pregnancies between January 1997 and March 2011 in women with primary infertility were retrieved from a prospective data collection. Four cohorts were constructed based on exposure to hysteroscopy and pregnancy outcome (early miscarriage vs live birth). The primary endpoint was the duration of pregnancy at 37 weeks. Pregnancy outcomes of 167 infertile patients exposed to cervical dilation and hysteroscopy were compared with those of 327 infertile women unexposed to hysteroscopy. RESULTS: The incidence of miscarriage, preterm birth, placenta previa, and premature rupture of membranes after maternal exposure to hysteroscopy was similar to that in women not exposed. CONCLUSION: Prior hysteroscopy in infertile women does not affect subsequent pregnancy outcome.

[When to Stop Contraception - Reasons and Consequences of Delaying Parenthood]. / Verhüten bis es (fast) zu spät ist ­ Gründe und Konsequenzen eines Aufschubs der Elternschaft.

When to Stop Contraception - Reasons and Consequences of Delaying Parenthood Abstract. Women are delaying motherhood for many reasons. However, knowledge on age-related decline of fertility is limited. Many patients and even physicians are not aware that female fertility starts to diminish significantly after the age of thirty-two years, and success rates of in vitro treatment are overestimated in the general population. Apart from maternal age there is no predictor for future fecundity. Physicians should actively discuss reasons for delaying motherhood and options for improving fecundity. During the reproductive life span, women need reliable counselling on contraception and fertility.

Menopausal state in breast cancer: how reliable is the data?

UNLABELLED: Despite the high importance of the menopausal state for the management of breast cancer, above all, when planning antihormonal adjuvant therapy, the menopausal state cannot be defined at the time of diagnosis ina significant proportion of women. The scope of uncertainties regarding the recording of the menopausal state in a cohort of patients with breast cancer is evaluated. INTRODUCTION: Menopause is a cornerstone both in breast cancer (BC) pathophysiology and in clinical management. The scope of uncertainties regarding the recording of the menopausal state in a cohort of patients with BC is evaluated in this study. PATIENTS AND METHODS: The data of a Swiss prospective relational BC database that covered a 20-year period (1990-2009; n=1457) was analyzed. For the definition of menopause, the guidelines of the National Comprehensive Cancer Network were used. RESULTS: The menopausal state was unclear in 150 patients (10.2%). Of these, 122 (81.3%) had undergone a hysterectomy before menopause; in 28 women (18.7%), an endocrine therapy obscured the patient's actual endocrine status. When taking only the subgroup of women in which menopause usually occurs (45-55 years) into consideration, the menopausal state was unclear in 91 cases of 337 women (27.0%). From the entire cohort, the date of last menstruation remained obscure in 450 patients (30.9%). CONCLUSION: Despite the high importance of the menopausal state for the management of BC, above all, when planning antihormonal adjuvant therapy, the menopausal state was unable to be defined at the time of BC diagnosis in a significant proportion of women. The dilemma that menopause cannot be assessed in some BC cases is increasingly being recognized. Close cooperation between oncologists and endocrinologists is desirable to establish an optimal, individually tailored therapy for women with an unclear menopausal state due to hormonal therapies, hysterectomy, or chemotherapy.

Combined array comparative genomic hybridization and tissue microarray analysis suggest PAK1 at 11q13.5-q14 as a critical oncogene target in ovarian carcinoma.

Amplification of chromosomal regions leads to an increase of DNA copy numbers and expression of oncogenes in many human tumors. The identification of tumor-specific oncogene targets has potential diagnostic and therapeutic implications. To identify distinct spectra of oncogenic alterations in ovarian carcinoma, metaphase comparative genomic hybridization (mCGH), array CGH (aCGH), and ovarian tumor tissue microarrays were used in this study. Twenty-six primary ovarian carcinomas and three ovarian carcinoma cell lines were analyzed by mCGH. Frequent chromosomal overrepresentation was observed on 2q (31%), 3q (38%), 5p (38%), 8q (52%), 11q (21%), 12p (21%), 17q (21%), and 20q (52%). The role of oncogenes residing in gained chromosomal loci was determined by aCGH with 59 genetic loci commonly amplified in human tumors. DNA copy number gains were most frequently observed for PIK3CA on 3q (66%), PAK1 on 11q (59%), KRAS2 on 12p (55%), and STK15 on 20q (55%). The 11q13-q14 amplicon, represented by six oncogenes (CCND1, FGF4, FGF3, EMS1, GARP, and PAK1) revealed preferential gene copy number gains of PAK1, which is located at 11q13.5-q14. Amplification and protein expression status of both PAK1 and CCND1 were further examined by fluorescence in situ hybridization and immunohistochemistry using a tissue microarray consisting of 268 primary ovarian tumors. PAK1 copy number gains were observed in 30% of the ovarian carcinomas and PAK1 protein was expressed in 85% of the tumors. PAK1 gains were associated with high grade (P < 0.05). In contrast, CCND1 gene alterations and protein expression were less frequent (10.6% and 25%, respectively), suggesting that the critical oncogene target of amplicon 11q13-14 lies distal to CCND1. This study demonstrates that aCGH facilitates further characterization of oncogene candidates residing in amplicons defined by mCGH.