The Effects of Separate and Combined Treatment of Male Rats with Type 2 Diabetes with Metformin and Orthosteric and Allosteric Agonists of Luteinizing Hormone Receptor on Steroidogenesis and Spermatogenesis.

In men with type 2 diabetes mellitus (T2DM), steroidogenesis and spermatogenesis are impaired. Metformin and the agonists of luteinizing hormone/human chorionic gonadotropin(hCG)-receptor (LH/hCG-R) (hCG, low-molecular-weight allosteric LH/hCG-R-agonists) can be used to restore them. The aim was to study effectiveness of separate and combined administration of metformin, hCG and 5-amino-N-tert-butyl-2-(methylsulfanyl)-4-(3-(nicotinamido)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide (TP3) on steroidogenesis and spermatogenesis in male rats with T2DM. hCG (15 IU/rat/day) and TP3 (15 mg/kg/day) were injected in the last five days of five-week metformin treatment (120 mg/kg/day). Metformin improved testicular steroidogenesis and spermatogenesis and restored LH/hCG-R-expression. Compared to control, in T2DM, hCG stimulated steroidogenesis and StAR-gene expression less effectively and, after five-day administration, reduced LH/hCG-R-expression, while TP3 effects changed weaker. In co-administration of metformin and LH/hCG-R-agonists, on the first day, stimulating effects of LH/hCG-R-agonists on testosterone levels and hCG-stimulated expression of StAR- and CYP17A1-genes were increased, but on the 3-5th day, they disappeared. This was due to reduced LH/hCG-R-gene expression and increased aromatase-catalyzed estradiol production. With co-administration, LH/hCG-R-agonists did not contribute to improving spermatogenesis, induced by metformin. Thus, in T2DM, metformin and LH/hCG-R-agonists restore steroidogenesis and spermatogenesis, with metformin being more effective in restoring spermatogenesis, and their co-administration improves LH/hCG-R-agonist-stimulating testicular steroidogenesis in acute but not chronic administration.

Hyperprolactinemia and Antipsychotic Therapy in Schizophrenic Patients with Hashimoto's Thyroiditis.

INTRODUCTION: Hyperprolactinemia (HPRL) is known as a side effect of some antidepressants and antipsychotics. These medicines are common in treatment of schizophrenia. Thus, HPRL is often observed in schizophrenic patients. It is also known that HPRL can occur in Hashimoto's thyroiditis due to prolactoliberin effect of thyroliberin. The clinical pathophysiology of the patients with the comorbidity of schizophrenia and Hashimoto's thyroiditis, receiving antipsychotics, is of special interest. It's fair to assume that these patients have higher risks of HPRL. To analyze risks of HPRL with antipsychotic treatment, to identify an association between the antipsychotic therapy (AT) and HPRL in Hashimoto's patients receiving AT, to explore the association of HPRL and other laboratory parameters in patients with Hashimoto's thyroiditis and schizophrenia during AT. SUBJECTS AND METHODS: We studied 17 patients with HT in comorbidity with schizophrenia receiving AT (mean age 46.5±12.8 years), all euthyroid or with light hypothyroidism. Different laboratory parameters such as anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-TG) antibodies, blood levels of thyroid stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3) and prolactin (PRL) were analysed. RESULTS: The study revealed the high levels of PRL, anti-TPO and anti-TG autoantibodies. Thus, patients were classified into 3 groups by the degree of expected HPRL risk from the antipsychotics used: without expected risk, with low and high expected risks. The correlation analysis detected an inverse significant correlation (R=-0.51; p=0.037) between expected level of drug-associated HPRL risk and actual PRL levels in studied group. At the same time, we detected a positive significant correlation between the levels of PRL and FT4 in the groups (R=0.53; p=0.03). The correlations between the levels of PRL and other parameters such as TSH, FT3, anti-TPO, anti-TG, anti-TSH receptor antibodies were not statistically significant. CONCLUSIONS: HPRL in the group was not associated with taking of antipsychotic drugs with high expected HPRL risk. Yet, a significant positive correlation existed between the levels of PRL and FT4. Hence, in Hashimoto's thyroiditis accompanied with treated mental illness there are some non-iatrogenic stimulants of prolactogenesis. It cannot be ruled out that antipsychotics may interfere with prolactin metabolism, which creates a false effect of a positive correlation between prolactin and free thyroxine levels, in contrast to common HPRL of hypothyroidism.

Comparative Study of the Steroidogenic Effects of Human Chorionic Gonadotropin and Thieno[2,3-D]pyrimidine-Based Allosteric Agonist of Luteinizing Hormone Receptor in Young Adult, Aging and Diabetic Male Rats.

Low-molecular-weight agonists of luteinizing hormone (LH)/human chorionic gonadotropin (hCG) receptor (LHCGR), which interact with LHCGR transmembrane allosteric site and, in comparison with gonadotropins, more selectively activate intracellular effectors, are currently being developed. Meanwhile, their effects on testicular steroidogenesis have not been studied. The purpose of this work is to perform a comparative study of the effects of 5-amino-N-tert-butyl-4-(3-(1-methylpyrazole-4-carboxamido)phenyl)-2-(methylthio)thieno[2,3-d] pyrimidine-6-carboxamide (TP4/2), a LHCGR allosteric agonist developed by us, and hCG on adenylyl cyclase activity in rat testicular membranes, testosterone levels, testicular steroidogenesis and spermatogenesis in young (four-month-old), aging (18-month-old) and diabetic male Wistar rats. Type 1 diabetes was caused by a single streptozotocin (50 mg/kg) injection. TP4/2 (20 mg/kg/day) and hCG (20 IU/rat/day) were administered for 5 days. TP4/2 was less effective in adenylyl cyclase stimulation and ability to activate steroidogenesis when administered once into rats. On the 3rd-5th day, TP4/2 and hCG steroidogenic effects in young adult, aging and diabetic rats were comparable. Unlike hCG, TP4/2 did not inhibit LHCGR gene expression and did not hyperstimulate the testicular steroidogenesis system, moderately increasing steroidogenic proteins gene expression and testosterone production. In aging and diabetic testes, TP4/2 improved spermatogenesis. Thus, during five-day administration, TP4/2 steadily stimulates testicular steroidogenesis, and can be used to prevent androgen deficiency in aging and diabetes.