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Sołtysik et al. show that the inner nuclear membrane of nonhepatocytes harbors triglyceride synthesis enzymes and generates nuclear lipid droplets (LDs). Seipin knockdown increases nuclear LDs through upregulating lipin-1β transcription and increasing phosphatidic acid levels in the nucleus., Nuclear lipid droplets (LDs) in hepatocytes are derived from precursors of very-low-density lipoprotein in the ER lumen, but it is not known how cells lacking the lipoprotein secretory function form nuclear LDs. Here, we show that the inner nuclear membrane (INM) of U2OS cells harbors triglyceride synthesis enzymes, including ACSL3, AGPAT2, GPAT3/GPAT4, and DGAT1/DGAT2, and generates nuclear LDs in situ. mTOR inhibition increases nuclear LDs by inducing the nuclear translocation of lipin-1 phosphatidic acid (PA) phosphatase. Seipin, a protein essential for normal cytoplasmic LD formation in the ER, is absent in the INM. Knockdown of seipin increases nuclear LDs and PA in the nucleus, whereas seipin overexpression decreases these. Seipin knockdown also up-regulates lipin-1β expression, and lipin-1 knockdown decreases the effect of seipin knockdown on nuclear LDs without affecting PA redistribution. These results indicate that seipin is not directly involved in nuclear LD formation but instead restrains it by affecting lipin-1 expression and intracellular PA distribution.

Objective Estrogen replacement therapy (ERT) for Turner syndrome (TS) is a widely discussed topic; however, the optimal model of ERT for patients with delayed diagnosis and/or initiation of therapy is still unclear, mainly due to insufficient data. We present the results of a prospective observational single-center study in which the efficacy of late-onset puberty induction by one-regimen transdermal ERT in TS girls was evaluated. Methods The analysis encompassed 49 TS girls (63.3% with 45,X) with hypergonadotropic hypogonadism in whom unified transdermal ERT protocol was used for puberty induction (first two months 12.5 μg/24 h, thereafter 25.0 μg/24 h until breakthrough bleeding). Clinical visits for examination and therapy modification took place every 3–6 months. Transabdominal pelvic ultrasound examinations were performed at least twice: at the beginning and at the end of follow-up. Results The mean (SD) age at ERT induction was 15.1 (1.3) years. The duration of follow-up was 2.4 (1.1) years. Half of all the patients had at least B2 after 0.57 years, B3 after 1.1 years, B4 after 1.97 years, and menarche after 1.82 years from ERT initiation. With earlier initiation of ERT (≤14 years), B2 (p = 0.059) was achieved faster and B4 (p = 0.018) significantly slower than with the later start of ERT. Thirty-four (94.4%) patients had at least stage B3 at menarche. The karyotype, initial weight, and body mass index had no impact on puberty tempo during ERT. The uterine volume increased significantly during ERT in all the study group (p 14 years). Conclusion The presented easy-to-use fixed-dose regimen for late-onset puberty induction allowed for a satisfactory rate of achieving subsequent puberty stages and did not influence the growth potential.

Aims: To investigate whether karyotype, mid-childhood (6–10 years) follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, and ultrasound ovary visualization results can be used as indicators of spontaneous puberty in Turner syndrome (TS). Methods: The analysis was based on clinical and biochemical data from 110 TS girls aged >13 years at the end of the study (1,140 visits between 1996 and 2015). The study population was divided according to karyotype: 45,X and non-45,X. Results: The mean age ± standard deviation at diagnosis was 10.7 ± 4.0 years, and the follow-up duration was 5.9 ± 3.3 years. Spontaneous puberty was confirmed in 48% and menarche in 20% of the subjects, less frequently in 45,X girls. The mean age at Tanner stage B2 was 13.7 ± 2.4 years and that at menarche 14.2 ± 1.7 years, regardless of the karyotype. The median FSH level at 6–10 years was 8.16 IU/L, which was significantly lower than 10 years. The median LH level at 6–10 years was 0.35 IU/L, which was lower than >10 years. The chance of spontaneous menarche was decreased in girls with FSH ≥6.7 IU/L between 6 and 10 years. Conclusions: Although spontaneous puberty and menarche occur more frequently in non-45,X girls, the karyotype cannot be used to predict them. However, the chance of spontaneous menarche can be predicted based on gonadotropin cut-off values. There was no correlation between ultrasound ovary visualization results and spontaneous puberty.

Lipid droplets (LDs) are often found adjacent to the endoplasmic reticulum (ER). The ER-LD association may appear morphologically similar to the prototypical membrane contact sites found between the ER and other organelles, but the functional relationship between the ER and LDs is unique in that highly hydrophobic lipid esters are transported between them. This transportation is thought to occur through some form of membrane continuity, but its details are yet to be defined. Lipin, seipin, and FIT proteins, which are located at the ER-LD interface, may be involved in the lipid ester transport and probably play important roles for functional connectivity of the two organelles. More recently, LDs in the nucleus were found to be closely adhered to the inner nuclear membrane, representing a specialized form of the ER-LD association. In this article, we will give an overview of the ER-LD association, which is still filled with many unanswered questions.

The lipid droplet (LD) is a cytoplasmic organelle, but it also exists in the nucleus under some conditions or in some cell types. New studies have revealed that nuclear LDs do not occur by haphazard entry of cytoplasmic LDs. Instead, they are generated by specific mechanisms that are increasingly understood. The inner nuclear membrane (INM) plays a critical role in nuclear LD formation in both mammalian hepatocytes and budding yeast, although in significantly different ways. Hepatocyte nuclear LDs derive from precursors of very low-density lipoprotein lacking apolipoprotein B-100, which form in the endoplasmic reticulum lumen and accumulate in intranuclear extensions of the perinuclear space called type I nucleoplasmic reticulum. In contrast, nuclear LDs in yeast are generated by triglyceride synthesized in the INM. Nuclear LDs in hepatocytes and budding yeast are both instrumental in the regulation of phospholipid synthesis; however, again they function in different ways. As the full functional importance is as yet unknown, the close relationship of nuclear LDs and the INM is an attractive target of research from both physiological and pathological perspectives.

Objectives: Certain therapies with the use of analogs of gonadotropin-releasing hormone (GnRH, gonadoliberin) aim at achieving the effect of desensitization of the pituitary gland that causes inhibition of the hypothalamicpituitary-gonadal axis. The resulting hormonal changes may influence the location and expression of estrogen and progesterone receptors, as well as their endogenous functions. The aim: The aim of the study was to investigate whether long-term administration of low doses of dalarelin (GnRH agonist) and cetrorelix (GnRH antagonist) affected subcellular and tissue-specific location of ERα and ERβ estrogen receptors and progesterone receptor (PR) in rat uterus, as well as explore the extent to which the changes were reversible. Material and methods: Analogs were administered to SPD adult females in the course of 3 months, at a dose of 6 μg/kg b.w. Afterwards, the ovaries and the uterus were resected – in the course of 4 weeks after treatment completion. Tissue paraffin-embedded samples were stained with hematoxyline-eosin for morphological studies or incubated with specific antibodies for the immunohistochemical studies (ABC method). Results: GnRH analogs induced desensitization, resulting in specific and relatively persistent histological changes in the ovaries and the uterus. Strong nuclear reaction for ERα in the lining and the glandular epithelial cells in dalarelintreated rats, and lack of expression changes in cetrorelix-treated rats, were observed in the uterus. Epithelial ERα expressions were accompanied by diminished ERβ and elevated PR expression, as well as diminished ERα andERβ expression, and unchanged PR expression in the stromal and muscle cells, in both dalarelin- and cetrorelixtreatedrats. The majority of the changes were reversible after treatment discontinuation. Conclusions: Long-term exposure to low doses of GnRH analogs causes morphological changes in the uterine tissues, accompanied by reversible changes of the ERα, ERβ and PR expression, possibly influencing tissue sensitivity. These changes indicate that agonist and antagonist regulate ERα expression by means of different mechanisms. A functional interaction between the receptors, depending on ERβ expression, direct influence of analogs on the local hormonal axes, and dose-dependent effects, cannot be excluded. After discontinuation of the analog treatment, the time needed for stabilization of ER and PR expression is shorter than the period of time required to restore histological structure of the uterus.