Diabetes mellitus and female sexual response: what do animal models tell us?

BACKGROUND: One of the less explored effects of diabetes mellitus (DM) is female sexual dysfunction. Females of different species have been used as models. AIM: To analyze the information of animal models of DM and female sexual response (FSR). METHODS: The literature of FSR in models of DM was reviewed. OUTCOMES: Paradigm- and diabetes-dependent changes have been found in various aspects of the FSR. RESULTS: Females in a type 1 DM (DM1) model show a decrease in the number of proestrus events, and ovariectomized females treated with sex hormones have been used. In these females, a reduction in lordosis has been reported; in proceptivity, the data are contradictory. These females present a decrease in sexual motivation that was restored after exogenous insulin. In the type 2 DM (DM2) model, females show regular estrous cycles, normal levels of lordosis behavior, and, depending on the paradigm, decreased proceptivity. These females display normal preference for sexually active males or their olfactory cues when having free physical contact; they lose this preference when tested in paradigms where physical interaction is precluded. CLINICAL TRANSLATION: Preclinical data showing the high deleterious effects of a DM1 model and the less drastic effects under a DM2 model are in accordance with clinical data revealing a much higher prevalence of sexual dysfunction in women with DM1 than DM2. STRENGTHS AND LIMITATIONS: The main strength is the analysis of the changes in various components of FSR in 2 models of DM. The main limitation is the difficulty in extrapolating the data on FSR from rats to women and that most studies focus on evaluating the impact of severe or chronic-moderate hyperglycemia/hyperinsulinemia on the sexual response, without considering other pathophysiologic alterations generated by DM. CONCLUSION: Females with severe hyperglycemia have a decrease in FSR, while those with moderate hyperglycemia show much less drastic effects.

Chronic moderate hyperglycemia does not alter sexual motivation in the female rat.

The relationship between diabetes mellitus type 2 (DM2) and sexual desire in women has not been systematically studied, therefore, animal models have been used for this purpose. When streptozotocin (STZ) is administered in the neonatal stage, the rat shows moderate chronic hyperglycemia and glucose intolerance in adulthood, resembling a DM2 model. These females show less alterations of sexual behavior (a slight decreased proceptivity and loss of paced mating) than their counterpart with severe hyperglycemia. However, the motivational components of copulation in female rats in this DM2 model have not been examined. The aim of this study was to evaluate female sexual motivation in a model of DM2 in three behavioral paradigms: the partner preference (PP), the sexual incentive motivation (SIM) and the odor preference test (OPT) tests. Neonatal females (3-4 days) were administered with streptozotocin (STZ, 70 mg/kg, intraperitoneally) or citrate buffer. At week 8, a glucose tolerance test was performed, females with blood glucose levels ≥ 250 mg/dl 60 min after a sucrose load (2 g/kg) were considered for the study. Behavioral tests were conducted at week 12, when the females were in natural proestrus. For PP we registered the time in each compartment and the sexual behavior, while in the SIM test, we calculated the time the females remained in each incentive zone. In these tests a castrated male and a sexually experienced male were used as stimuli. In OPT we evaluated the time the females spent sniffing the sawdust coming from cages housing these stimuli. In the PP and OPT hyperglycemic females behave similarly than controls, i.e., they retain a preference for sexually active males. In the SIM test there was a decrease in the time the hyperglycemic females remain in the vicinity of the sexually expert male. Data are discussed on the bases of the accessibility of the females to the stimuli.

Diabetic female rats exhibit defensive aggression during mating / Las ratas hembra diabéticas exhiben agresión defensiva durante la cópula

Abstract Introduction Few reports have analyzed the putative association between diabetes mellitus type 1 (DM1) and aggressiveness. A previous study using a model of DM1 reported an increase in aggressive behaviors (AB) of females against the male during mating, which was prevented by insulin. However, it was unclear if such aggression was defensive or offensive. Objective To evaluate the different components of aggressiveness of hyperglycemic female rats in two distinct mating paradigms. Method DM1 was modeled in OVX Wistar rats by injecting streptozotocin (STZ) diluted in citrate buffer (50 mg/kg, i.p., for 2 consecutive days). Ten days later, female rats were treated with estradiol benzoate (10 microg, -24 hours) and progesterone (3 mg, -4 hours). A group of STZ-treated animals was administered with a long-acting insulin analogue (glargine) every 12 hours for 8 days. Aggression was recorded in non-paced mating (NPM) and paced mating (PM) paradigms. We registered: the first attack latency (FAL), the proportion of females that presented AB and its type (boxing, bites, lateral kicks and twist) and if AB were exhibited defensively or offensively. Results Hyperglycemic rats showed an increase in lateral kicks in NPM, whereas in PM they exhibited an increase in bites. These behaviors were always defensive and there were no changes in FAL. Insulin reduced AB. Discussion and conclusion Data indicate that the aggressiveness of hyperglycemic female rats is a form of defense against the proximity of the male and add information about the role of insulin on their modulation.

Resumen Introducción Pocos trabajos han evaluado la relación entre diabetes mellitus tipo 1 (DM1) y la agresividad. En un estudio se reportó un aumento en las conductas agresivas (CA) de las hembras contra el macho durante la cópula, las cuales se reducen administrando insulina. No está claro si estas CA se expresan de manera defensiva u ofensiva. Objetivo Evaluar diferentes componentes de la agresividad de ratas hembras hiperglucémicas en dos paradigmas de cópula. Método La DM1 fue modelada en ratas Wistar ovariectomizadas inyectando estreptozotocina (STZ) disuelta en buffer de citratos (50 mg/kg, i.p., durante dos días consecutivos). Diez días después, se les administró benzoato de estradiol (10 microg, -24 horas) y progesterona (3 mg, -4 horas). A un grupo tratado con STZ se le administró un análogo de insulina (glargina) cada 12 horas durante ocho días. La agresión se registró en los paradigmas de cópula no regulada (NPM) y regulada (PM). Se registraron: la latencia al primer ataque (LPA), la proporción de hembras que exhibieron alguna CA, el tipo (boxeo, mordidas, patadas laterales y giros) y si se presentaron de manera defensiva u ofensiva. Resultados Las hembras diabéticas mostraron un aumento en las patadas laterales en NPM mientras que en PM exhibieron más mordidas. Las conductas fueron defensivas, no hubo cambios en la LPA. La insulina redujo la expresión de CA. Discusión y conclusión Los datos indican que las CA de las hembras hiperglucémicas son una forma de defensa contra la proximidad del macho y agregan información sobre el papel de la insulina en su modulación.

Does Chronic Hyperglycemia Affect Female Rat Sexual Behavior? Differences in Paced and Non-Paced Mating.

INTRODUCTION: Diabetes mellitus has been associated with sexual dysfunction; however, in women this relationship is controversial. A study using a model of type 2 diabetes mellitus (DM2) failed to find a reduced receptivity in the non-paced mating (NPM), but the appetitive aspects of female sexual behavior have not been evaluated, for example, in the paced mating (PM) paradigm. AIM: To evaluate all components of female sexual behavior (in NPM and PM) in a model of DM2 using ovariectomized (OVX) (treated with steroids) or intact female rats (non-OVX) in natural proestrus. METHODS: Neonatal females (3-4 days) were administered streptozotocin (STZ, 70 mg/kg, intraperitoneally) or citrate buffer. At week 8, a glucose tolerance test was performed. At week 10, half of the females were OVX, and in the other half (non-OVX) the estrous cycle was monitored. At the twelfth week, the sexual behavior tests were conducted; OVX females were treated with estradiol benzoate (10 µg, -24 hours) and progesterone (3 mg, -4 hours), whereas the non-OVX were evaluated on vaginal proestrus. MAIN OUTCOME MEASURES: We registered in NPM and PM receptivity (lordosis quotient and intensity), as well as the number of proceptive and aggressive behaviors. Additionally, in PM we calculated the percentage of exits and the return latencies after receiving stimulation and the time the female remained in the male's compartment. RESULTS: The STZ-treated females presented glucose intolerance and were hyperglycemic. Neonatal STZ treatment provoked changes in the females' sexual behavior depending on the paradigm and the hormonal condition. In the NPM, STZ-OVX females had decreased lordosis quotient and intensity and increased aggression, whereas, in the STZ-non-OVX females, there was a decrease in proceptivity; such changes were not observed in PM. Regardless of whether the STZ-treated females were OVX, they failed to perform the pacing behavior. CLINICAL IMPLICATION: These data support the idea that chronic mild hyperglycemia, like that observed in DM2 (which represents 90% of the clinical cases), provokes marginal changes in most aspects of female sexual behavior. STRENGTHS & LIMITATIONS: The main strength of this work is the evaluation of consummatory and motivational aspects of female sexual behavior in a model of DM2. The main limitation is the duration of the experimental design that does not resemble the course of the disease in humans. No histologic or biochemical analyses were performed. CONCLUSION: These results suggest that chronic hyperglycemia produces decreases in sexual behavior. Hernández-Munive AK, Rebolledo-Solleiro D, Fernández-Guasti A. Does Chronic Hyperglycemia Affect Female Rat Sexual Behavior? Differences in Paced and Non-Paced Mating. J Sex Med 2019;16:1130-1142.

Reduced Lordosis and Enhanced Aggression in Paced and Non-Paced Mating in Diabetic Female Rats.

BACKGROUND: Clinical studies have shown altered sexual function in people with diabetes; basic science studies, using the streptozotocin (STZ)-induced animal model of type 1 diabetes mellitus (DM1), have consistently reported decreased sexual behavior in hyperglycemic female animals, but features of sexual motivation and aggressive behavior have not been explored in these animals. AIM: To study several parameters that denote sexual motivation in STZ-treated female rats and to compare behavioral features of sexual behavior and aggression in non-paced mating (NPM) and paced mating (PM) conditions. METHODS: DM1 was induced by injecting STZ (diluted in citrate buffer) at a dose of 50 mg/kg intraperitoneally over 2 consecutive days into ovariectomized Wistar rats. 10 days later, female rats were treated with estradiol benzoate (10 µg, -24 hours) and progesterone (3 mg, -4 hours); their sexual behavior (including lordosis quotient, lordosis intensity, and proceptivity) and aggression were evaluated under NPM and PM conditions. Body weight, blood glucose levels, and spontaneous ambulatory activity also were measured. A group of STZ-treated animals was administered a long-acting insulin analogue (glargine) every 12 hours for 8 days, and their sexual and aggressive behaviors were evaluated in NPM. OUTCOMES: We quantified body weight, blood glucose level, spontaneous ambulatory activity, and sexual and aggressive behaviors in NPM and PM; the time the female rats spent interacting with the male rat or in the male rat's chamber also was registered in PM. RESULTS: Compared with controls, STZ-treated ovariectomized rats lost body weight, had increased blood glucose levels, and had unchanged spontaneous ambulatory activity. In the PM and NPM conditions, animals showed decreased lordosis quotient and lordosis intensity, increased aggression, and unaltered proceptivity, although in NPM the effects of STZ treatment on aggression were more drastic and were completely prevented by insulin. In PM no differences were found between diabetic and control female rats in the time interacting with the male rat or in the male rat's chamber. CLINICAL TRANSLATION: These findings support the observation of increased prevalence of sexual dysfunctions and aggression in the clinical setting of DM1. STRENGTHS AND LIMITATIONS: The main strength of this study is that it analyzed sexual behavior under PM and NPM conditions and aggression in STZ-treated female rats. Its main limitations are that the model of DM1 represents only 10% of the affected population and that no specific treatment is proposed for the sexual dysfunctions. CONCLUSION: These results suggest that STZ-treated rats have decreased sexual receptivity in NPM and PM, accompanied by increased aggressiveness in NPM. Hernández-Munive AK, Rebolledo-Solleiro D, Ventura-Aquino E, Fernández-Guasti A. Reduced Lordosis and Enhanced Aggression in Paced and Non-Paced Mating in Diabetic Female Rats. J Sex Med 2018;15:124-135.

Synthesis, antinociceptive and anti-inflammatory effects of porphyrins.

Porphyrins are natural compounds with several biological activities. We report the synthesis and the evaluation of the anti-inflammatory and antinociceptive effects of 4 porphyrins: 5,10,15,20-tetraphenylporphyrin (TPP), 5,10,15,20-tetra(4'-fluorophenyl)porphyrin (TpFPP), 5,10,15,20-tetra(4'-chlorophenyl)porphyrin (TpClPP), and 5,10,15,20-tetra(4'-bromophenyl)porphyrin (TpBrPP). The in vitro anti-inflammatory effects were evaluated on heat-induced hemolysis. The antinociceptive effects were evaluated using the hot plate and formalin tests. The in vivo anti-inflammatory assays were tested on the acute and chronic TPA (12-O-tetradecanoylphorbol 13-acetate) method to induce ear edema. The anti-arthritic effects were evaluated using carrageenan kaolin induced arthritis (CKIA). All porphyrins inhibited hemolysis with similar potency than naproxen (NPX). In the antinociceptive tests, all porphyrins tested at 200mg/kg showed similar effects compared to 100mg/kg NPX. In the in vivo anti-inflammatory acute assay, only three porphyrins (TPP, TpFPP and TpBrPP) decreased inflammation with similar activity than 2mg/ear indomethacin (IND). Further anti-inflammatory experiments were carried out with TPP, TpFPP and TpBrPP. In the in vivo anti-inflammatory chronic assay, porphyrins decreased inflammation with similar activity than 8mg/kg IND. Porphyrins tested at 200mg/kg showed anti-arthritic effects. The antinociceptive, anti-inflammatory and arthritic activities of porphyrins suggest that these compounds might be a good alternative for the treatment of inflammatory diseases.

Antidiarrheal activity of 19-deoxyicetexone isolated from Salvia ballotiflora Benth in mice and rats.

The antidiarrheal properties of 19-deoxyicetexone, a diterpenoid isolated from Salvia ballotiflora were evaluated on castor oil-, arachidonic acid (AA)- and prostaglandin (PGE2)-induced diarrhea in rodent models. The structure of 19-deoxyicetexone was determined by X-ray crystallography, mass spectrometry (EI-MS), as well as ultraviolet (UV-Vis), infrared (FT-IR) and nuclear magnetic resonance (NMR) spectroscopies. This compound significantly and dose-dependently reduced frequency of stooling in castor oil-induced diarrhea, and at dose of 25 mg/kg it also inhibited diarrhea induced with AA, while it had no effect on PGE2-induced diarrhea. This compound at doses of 25 mg/kg also diminished castor oil-induced enteropooling and intestinal motility, and inhibited the contraction of the rats' ileum induced by carbachol chloride at a concentration of 100 µg/mL. 19-Deoxyicetexone did not present acute toxicity at doses of 625 mg/kg. Its antidiarrheal activity may be due to increased reabsorption of NaCl and water and inhibition of the release of prostaglandins, gastrointestinal motility and fluid accumulation in the intestinal tracts of rats. These findings suggest that 19-deoxyicetexone may be used in the treatment of diarrhea, although more studies must be carried out to confirm this.