Clinical Utility of GnRH Analogues in Female Androgen Excess: Highlighting Diagnostic and Therapeutic Applications.

Female androgen excess typically presents with hirsutism, acne, and frontotemporal alopecia. Although the majority of cases are due to underlying polycystic ovary syndrome, non-polycystic ovary syndrome pathology can present a diagnostic and therapeutic challenge. We present 3 cases highlighting the utility of GnRH analogues in diagnosis and treatment of ovarian hyperandrogenism. In case 1, we highlight the role of GnRH analogue testing to localize severe postmenopausal androgen excess, allowing full resolution of symptoms following resection of a benign ovarian steroid-cell tumor. Our second case demonstrates the dual utility of GnRH analogues as both a diagnostic and therapeutic agent for hyperandrogenism in a premenopausal woman with severe insulin resistance. We observed suppression of serum testosterone coupled with significant improvement in hirsutism scores. The final case describes GnRH analogue suppression as a therapeutic option for a postmenopausal woman with ovarian hyperthecosis wishing to avoid surgical intervention, with successful symptom resolution. This case series delineates the applications of GnRH analogue suppression in a variety of clinical contexts, in particular their potential role in controlling symptoms in cases of refractory androgen excess and an alternative to surgery in cases of benign ovarian hyperandrogenism.

Characterizing skeletal muscle dysfunction in women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine condition affecting women. It has traditionally been viewed as a primarily reproductive disorder; however, it is increasingly recognized as a lifelong metabolic disease. Women with PCOS are at increased risk of insulin resistance (IR), type 2 diabetes mellitus, non-alcoholic fatty liver disease and cardiovascular disease. Although not currently a diagnostic criterion, IR is a cardinal pathophysiological feature and highly prevalent in women with PCOS. Androgens play a bidirectional role in the pathogenesis of IR, and there is a complex interplay between IR and androgen excess in women with PCOS. Skeletal muscle has a key role in maintaining metabolic homeostasis and is also a metabolic target organ of androgen action. Skeletal muscle is the organ responsible for the majority of insulin-mediated glucose disposal. There is growing interest in the relationship between skeletal muscle, androgen excess and mitochondrial dysfunction in the pathogenesis of metabolic disease in PCOS. Molecular mechanisms underpinning defects in skeletal muscle dysfunction in PCOS remain to be elucidated, but may represent promising targets for future therapeutic intervention. In this review, we aim to explore the role of skeletal muscle in metabolism, focusing particularly on perturbations in skeletal muscle specific to PCOS as observed in recent molecular and in vivo human studies. We review the possible role of androgens in the pathophysiology of skeletal muscle abnormalities in PCOS, and identify knowledge gaps, areas for future research and potential therapeutic implications. Despite increasing interest in the area of skeletal muscle dysfunction in women with PCOS, significant challenges and unanswered questions remain, and going forward, novel innovative approaches will be required to dissect the underlying mechanisms.

Approach to androgen excess in women: Clinical and biochemical insights.

Androgen excess in women typically presents clinically with hirsutism, acne or androgenic alopecia. In the vast majority of cases, the underlying aetiology is polycystic ovary syndrome (PCOS), a common chronic condition that affects up to 10% of all women. Identification of women with non-PCOS pathology within large cohorts of patients presenting with androgen excess represents a diagnostic challenge for the endocrinologist, and rare pathology including nonclassic congenital adrenal hyperplasia, severe insulin resistance syndromes, Cushing's disease or androgen-secreting tumours of the ovary or adrenal gland may be missed in the absence of a pragmatic screening approach. Detailed clinical history, physical examination and biochemical phenotyping are critical in risk-stratifying women who are at the highest risk of non-PCOS disorders. Red flag features such as rapid onset symptoms, overt virilization, postmenopausal onset or severe biochemical disturbances should prompt investigations for underlying neoplastic pathology, including dynamic testing and imaging where appropriate. This review will outline a proposed diagnostic approach to androgen excess in women, including an introduction to androgen metabolism and provision of a suggested algorithmic strategy to identify non-PCOS pathology according to clinical and biochemical phenotype.

HIST1H1E syndrome with type 2 diabetes.

A 20-year-old woman was referred to the diabetes clinic with type 2 diabetes diagnosed at the age of 19. Her body mass index was 31.4 kg/m2, HbA1C was 76 mmol/mol, GAD antibodies were negative with a detectable C-peptide. She had a characteristic facial appearance with widespread eyes, posterior hairline suggesting a facial gestalt and abnormal dentition. She also had hypothyroidism, mild intellectual disability, primary amenorrhoea and patent ductus arteriosus. Karyotyping reported normal 46XX karyotype. Genetic testing revealed a pathogenic variant in the gene encoding the HIST1H1E protein which confirmed her diagnosis of HIST1H1E syndrome. Type 2 diabetes has not been reported in previous cases of HIST1H1E and so this is the first reported case of type 2 diabetes with HIST1H1E syndrome.

NO Releasing and Anticancer Properties of Octahedral Ruthenium-Nitrosyl Complexes with Equatorial 1 H-Indazole Ligands.

With the aim of enhancing the biological activity of ruthenium-nitrosyl complexes, new compounds with four equatorially bound indazole ligands, namely, trans-[RuCl(Hind)4(NO)]Cl2·H2O ([3]Cl2·H2O) and trans-[RuOH(Hind)4(NO)]Cl2·H2O ([4]Cl2·H2O), have been prepared from trans-[Ru(NO2)2(Hind)4] ([2]). When the pH-dependent solution behavior of [3]Cl2·H2O and [4]Cl2·H2O was studied, two new complexes with two deprotonated indazole ligands were isolated, namely [RuCl(ind)2(Hind)2(NO)] ([5]) and [RuOH(ind)2(Hind)2(NO)] ([6]). All prepared compounds were comprehensively characterized by spectroscopic (IR, UV-vis, 1H NMR) techniques. Compound [2], as well as [3]Cl2·2(CH3)2CO, [4]Cl2·2(CH3)2CO, and [5]·0.8CH2Cl2, the latter three obtained by recrystallization of the first isolated compounds (hydrates or anhydrous species) from acetone and dichloromethane, respectively, were studied by X-ray diffraction methods. The photoinduced release of NO in [3]Cl2 and [4]Cl2 was investigated by cyclic voltammetry and resulting paramagnetic NO species were detected by EPR spectroscopy. The quantum yields of NO release were calculated and found to be low (3-6%), which could be explained by NO dissociation and recombination dynamics, assessed by femtosecond pump-probe spectroscopy. The geometry and electronic parameters of Ru species formed upon NO release were identified by DFT calculations. The complexes [3]Cl2 and [4]Cl2 showed considerable antiproliferative activity in human cancer cell lines with IC50 values in low micromolar or submicromolar concentration range and are suitable for further development as potential anticancer drugs. p53-dependence of Ru-NO complexes [3]Cl2 and [4]Cl2 was studied and p53-independent mode of action was confirmed. The effects of NO release on the cytotoxicity of the complexes with or without light irradiation were investigated using NO scavenger carboxy-PTIO.

A PET study examining pharmacokinetics and dopamine transporter occupancy of two long-acting formulations of methylphenidate in adults.

The delivery systems of two long-acting formulations of methylphenidate (MPH) were designed for different durations. Diffucaps bead-delivery system (DBDS)-MPH was designed to last 8 h and osmotically controlled-release oral delivery system (OROS)-MPH was designed to last 12 h. While the plasma pharmacokinetics and timing of efficacy have been studied, the corresponding central nervous system dopamine transporter (DAT) occupancies are unknown. In this study, 21 healthy volunteers underwent PET imaging with 11C Altropane before and after administration of oral doses of DBDS-MPH and OROS-MPH. Each subject received 40 mg DBDS-MPH and 36 mg OROS-MPH on different days. PET imaging occurred at 10 h after dosing. Each subject was injected with 5 mCi of 11C Altropane and serial images of the brain were acquired over 60 min with a Siemens HR+ PET camera. Binding potentials (BP, k3/k4) were calculated from time-activity curves using the simplified reference region method with cerebellum as reference. Transporter occupancy was calculated by standard methods. At 10 h, plasma d-MPH levels were lower (3.8+/-1.2 vs. 5.2+/-2.0) and brain DAT occupancy was lower (34.8+/-12.9 vs. 44.3+/-11.8) for DBDS-MPH than OROS-MPH. Across the range of values, for each unit of change in plasma d-MPH level there was a larger change in DAT occupancy with the DBDS-MPH formulation than with the OROS-MPH formulation. As predicted from previous pharmacokinetic and efficacy data, the average plasma level and DAT occupancy of 36 mg OROS-MPH was >40 mg DBDS-MPH at 10 h. Moreover, a relatively small difference in plasma levels (1.4 ng/ml at 10 h) was associated with a more impressive difference in DAT occupancy ( approximately 10% at 10 h).

An exploratory study of palliative care in bone marrow transplant patients.

Quality of life - as opposed to quantity of life - raises important issues for all concerned. The legal and moral issues surrounding death, and our new abilities to delay it, are discussed frequently in the press and in professional journals. It was therefore felt important within an acute bone marrow transplant unit to identify the factors which would be considered important in palliative care for post bone marrow transplant patients, with specific reference to quality of life. A questionnaire was designed to address certain issues surrounding the withdrawal of active treatment for this group of patients. The questionnaire content was derived from past experiences of caring for patients where death was imminent. It focuses on issues relating to patient advocacy, what is perceived as a good quality of life and the psychological implications for all concerned. This paper reports on a small exploratory study which aims to highlight key issues surrounding the withdrawal of active treatment when palliative care and symptom control take precedence.