RESUMO
BACKGROUND: Emergency contraception with levonorgestrel (LNG) is a viable option to prevent unintended pregnancies. Although the efficacy of LNG as an anovulatory agent decreases as treatment approaches ovulation, it still provides some contraceptive benefits. AIM: To better understand the contraceptive mechanisms of LNG in ovulatory subjects. METHODS: We conducted a study on Wistar rats that received a single dose of LNG (0.01 or 0.05 mg/kg) on the morning of proestrus before ovulation and evaluated its effects on ovarian gene expression, ovulation, and implantation. RESULTS: Our findings showed changes in the expression of genes involved in follicular development and oocyte quality. Pregnancy rates - as an indicator of ovulation - and embryo implantation were significantly lower than those in the control group. CONCLUSIONS: This study suggests that LNG alters regulatory factors in the ovary that are essential for the development of competent fertilizable oocytes, highlighting the non-anovulatory mechanisms by which levonorgestrel may regulate fertility and suggesting that it could be a novel observation that contributes to the understanding of emergency contraception in humans.
Assuntos
Levanogestrel , Ovário , Humanos , Gravidez , Feminino , Animais , Ratos , Levanogestrel/farmacologia , Ovário/fisiologia , Ratos Wistar , Anticoncepção , Anticoncepcionais/farmacologia , Expressão GênicaRESUMO
BACKGROUND: The high rates of unintended pregnancy and the ever-growing world population impose health, economic, social, and environmental threats to countries. Expanding contraceptive options, including male methods, are urgently needed to tackle these global challenges. Male contraception is limited to condoms and vasectomy, which are unsuitable for many couples. Thus, novel male contraceptive methods may reduce unintended pregnancies, meet the contraceptive needs of couples, and foster gender equality in carrying the contraceptive burden. In this regard, the spermatozoon emerges as a source of druggable targets for on-demand, non-hormonal male contraception based on disrupting sperm motility or fertilization. OBJECTIVE AND RATIONALE: A better understanding of the molecules governing sperm motility can lead to innovative approaches toward safe and effective male contraceptives. This review discusses cutting-edge knowledge on sperm-specific targets for male contraception, focusing on those with crucial roles in sperm motility. We also highlight challenges and opportunities in male contraceptive drug development targeting spermatozoa. SEARCH METHODS: We conducted a literature search in the PubMed database using the following keywords: 'spermatozoa', 'sperm motility', 'male contraception', and 'drug targets' in combination with other related terms to the field. Publications until January 2023 written in English were considered. OUTCOMES: Efforts for developing non-hormonal strategies for male contraception resulted in the identification of candidates specifically expressed or enriched in spermatozoa, including enzymes (PP1γ2, GAPDHS, and sAC), ion channels (CatSper and KSper), transmembrane transporters (sNHE, SLC26A8, and ATP1A4), and surface proteins (EPPIN). These targets are usually located in the sperm flagellum. Their indispensable roles in sperm motility and male fertility were confirmed by genetic or immunological approaches using animal models and gene mutations associated with male infertility due to sperm defects in humans. Their druggability was demonstrated by the identification of drug-like small organic ligands displaying spermiostatic activity in preclinical trials. WIDER IMPLICATIONS: A wide range of sperm-associated proteins has arisen as key regulators of sperm motility, providing compelling druggable candidates for male contraception. Nevertheless, no pharmacological agent has reached clinical developmental stages. One reason is the slow progress in translating the preclinical and drug discovery findings into a drug-like candidate adequate for clinical development. Thus, intense collaboration among academia, private sectors, governments, and regulatory agencies will be crucial to combine expertise for the development of male contraceptives targeting sperm function by (i) improving target structural characterization and the design of highly selective ligands, (ii) conducting long-term preclinical safety, efficacy, and reversibility evaluation, and (iii) establishing rigorous guidelines and endpoints for clinical trials and regulatory evaluation, thus allowing their testing in humans.
Assuntos
Anticoncepcionais Masculinos , Sêmen , Gravidez , Animais , Feminino , Masculino , Humanos , Ligantes , Anticoncepção/métodos , Anticoncepcionais/farmacologia , Espermatozoides , Anticoncepcionais Masculinos/farmacologiaRESUMO
The objective of this study was to evaluate the environmental effects on embryo recovery rate and pregnancy rate of Mangalarga Marchador mares. The reproductive characteristics of donor and recipient mares were evaluated during five years in Brazilian tropical environment. The mares were used throughout the year and seasons were classified as: October to April (breeding season - BS); May (autumn transition out of the breeding season - ATBS); June to August (non-breeding season - nBS); and September (vernal transition into the breeding season - VTBS). Daily temperature rainfall and hours of daylight (photoperiod) were measured during all months and years of evaluation. The embryo recovery rate (ERR) and the pregnancy rate (PR) were observed and frequencies were calculated. The effect of environmental variables, day of flushing, and hormonal treatments (estradiol benzoate and progesterone) were determined for the reproductive measures using the Chi-square and Kruskal-Wallis tests. Significant effects were noted of the year, season and temperature on ERR (Pâ¯<â¯0.05), but no significant effects were observed of the environmental parameters (year, season, hormone treatment, rainfall and photoperiod) on PR (Pâ¯>â¯0.05). The day of uterine flush affected ERR (Pâ¯<â¯0.05) but did not affect PR (Pâ¯>â¯0.05). In addition, hormone treatment also supported favorable results of PR in recipient mares during nBS. The conclusion is that mares of this breed can be used in reproduction all year long, with good pregnancy rates, in Brazil's tropical environment. The hormone treatment also supported favorable pregnancy rates in recipient mares during the non-breeding season. It seems that mares can have good pregnancy rates throughout the year in Brazil´s tropical environment.
Assuntos
Transferência Embrionária , Meio Ambiente , Cavalos/fisiologia , Animais , Brasil , Anticoncepcionais/administração & dosagem , Anticoncepcionais/farmacologia , Estradiol/administração & dosagem , Estradiol/análogos & derivados , Estradiol/farmacologia , Feminino , Ovulação/efeitos dos fármacos , Ovulação/fisiologia , Gravidez , Taxa de Gravidez , Progesterona/administração & dosagem , Progesterona/farmacologia , Doadores de Tecidos , Coleta de Tecidos e ÓrgãosRESUMO
BACKGROUND: Muscarinic receptors (mAChRs) of the preoptic and anterior hypothalamus areas (POA-AHA) regulate ovulation in an asymmetric manner during the estrous cycle. The aims of the present study were to analyze the effects of a temporal blockade of mAChRs on either side of the POA-AHA performed in diestrus-2 rats on ovulation, the levels of estradiol, follicle stimulating hormone (FSH) and luteinizing hormone (LH) and the mechanisms involved in changes in ovulation. METHODS: Cyclic rats on diestrus-2 day were anesthetized and randomly assigned to the following groups: 1) microinjection of 1 µl of saline or atropine solution (62.5 ng) in the left or right POA-AHA; 2) removal (unilateral ovariectomty, ULO) of the left (L-ULO) or right (R-ULO) ovary, and 3) rats microinjected with atropine into the left or right POA-AHA plus L-ULO or R-ULO. The ovulation rate and the number of ova shed were measured during the predicted estrus, as well as the levels of estradiol, FSH and LH during the predicted proestrus and the effects of injecting synthetic LH-releasing hormone (LHRH) or estradiol benzoate (EB). RESULTS: Atropine in the left POA-AHA decreased both the ovulation rate and estradiol and LH levels on the afternoon of proestrus, also LHRH or EB injection restored ovulation. L- or R-ULO resulted in a lower ovulation rate and smaller number of ova shed, and only injection of LHRH restored ovulation. EB injection at diestrus-2 restored ovulation in animals with L-ULO only. The levels of estradiol, FSH and LH in rats with L-ULO were higher than in animals with unilateral laparotomy. In the group microinjected with atropine in the left POA-AHA, ovulation was similar to that in ULO rats. In contrast, atropine in the right POA-AHA of ULO rats blocked ovulation, an action that was restored by either LHRH or EB injection. CONCLUSIONS: These results indicated that the removal of a single ovary at noon on diestrus-2 day perturbed the neuronal pathways regulating LH secretion, which was mediated by the muscarinic system connecting the right POA-AHA and the ovaries.
Assuntos
Núcleo Hipotalâmico Anterior/metabolismo , Diestro/metabolismo , Estradiol/metabolismo , Hormônio Foliculoestimulante/metabolismo , Hormônio Luteinizante/metabolismo , Ovulação/metabolismo , Área Pré-Óptica/metabolismo , Receptores Muscarínicos/metabolismo , Animais , Núcleo Hipotalâmico Anterior/efeitos dos fármacos , Atropina/farmacologia , Anticoncepcionais/farmacologia , Diestro/efeitos dos fármacos , Estradiol/análogos & derivados , Estradiol/farmacologia , Feminino , Hormônio Liberador de Gonadotropina/farmacologia , Hormônio Luteinizante/efeitos dos fármacos , Antagonistas Muscarínicos/farmacologia , Ovariectomia , Ovário/efeitos dos fármacos , Ovulação/efeitos dos fármacos , Área Pré-Óptica/efeitos dos fármacos , Proestro/efeitos dos fármacos , Proestro/metabolismo , Ratos , Receptores Muscarínicos/efeitos dos fármacosRESUMO
UNLABELLED: The present study evaluates the possible antifertility effect of aqueous crude extract (OBACE) of Echeveria gibbiflora, a plant that belongs to the crassulaceae family, used in traditional Mexican medicine as a vaginal post coital rinse to prevent pregnancy and shown to have an immobilization/agglutination effect on sperm of different mammal species. We evaluated the effect of OBACE on functional parameters of mouse sperm, such as viability, capacitation, and acrosome reaction. In addition, due to the high concentrations of calcium bis-(hydrogen-1-malate) hexahydrate [Ca (C4H5O5)2â¢6H2O] present in this plant extract, we evaluated its effect on Ca(2+) influx in mouse sperm under capacitating conditions. Moreover, we determined the acute toxicity of OBACE and its in vivo effect in mouse sperm motility administering a single daily dose of 50 and 100 mg/kg during seven days, intraperitoneally. The sperm viability was not affected by the presence of different concentrations of OBACE, however, the capacitation and acrosome reaction suffered a significant decrease in a concentration-dependent manner, coinciding with the reduction of Ca(2+) influx. Furthermore, OBACE displayed an LD50 of 3,784.42 mg/kg and can be classified as a low toxic substance. Also, in vivo OBACE showed an inhibition of total and progressive motility on mouse sperm alongside a significant decrease of motility kinematic parameters and IVF rates. The results confirm the antifertility effect of this plant used in Mexican folk medicine. Further study on OBACE as a possible contraceptive treatment is warranted because of its activity and low in vivo toxicity. ABBREVIATIONS: ALH: lateral amplitude; AP: acid phosphatase; BCF: beat frequency; BSA: bovine serum albumine; CTC: chlortetracycline; FDA: fluorescein diacetate; Fura-2 AM: fura-2-acetoxymethyl ester; HIV: human immunodeficiency virus; IVF: in vitro fertilization; OBACE: aqueous crude extract of Echeveria gibbiflora; PI: propidum iodide; SN: supernatant; VAP: average path velocity; VCL: track speed; VSL: straight line velocity.
Assuntos
Anticoncepcionais/farmacologia , Crassulaceae/química , Extratos Vegetais/farmacologia , Espermatozoides/efeitos dos fármacos , Reação Acrossômica/efeitos dos fármacos , Animais , Fertilização in vitro/efeitos dos fármacos , Masculino , Medicina Tradicional , México , Camundongos , Capacitação Espermática/efeitos dos fármacos , Motilidade dos Espermatozoides/efeitos dos fármacosRESUMO
OBJECTIVES: Feeding behavior in both animals and humans is modulated by estrogens, as shown by the increased adiposity observed in women and rats upon the drop of estradiol levels at menopause. Estradiol action on food intake is mediated through its cognate receptors within several hypothalamic nuclei, namely the arcuate nucleus (ARN). The ARN contains two neuronal populations expressing peptides that exert opposing effects on the central control of feeding: the orexigenic neuropeptide Y (NPY) and the anorexigenic α-melanocyte-stimulating hormone (α-MSH). METHODS: To understand the role played by estradiol in the modulation of food intake, we have used an animal model of cyclic 17ß-estradiol benzoate (EB) administration and stereological methods to estimate the total number of neurons immunoreactive for NPY and α-MSH in the ARN of ovariectomized rats. RESULTS: Present results show that the experimentally induced EB cyclicity prompted a decrease in food consumption and in body weight. Data also show that ovariectomy induced an increase in NPY expression and a decrease in α-MSH expression in the ARN that were reverted by EB administration. Conversely, EB blocked the expression of NPY and increased the synthesis of α-MSH in ARN neurons, without affecting the overall sum of NPY and α-MSH neurons. DISCUSSION: These results suggest that estradiol affects food intake and, consequently, body weight gain, through an overriding mechanism superimposed in the physiological balance between both peptides in the ARN of female rats.
Assuntos
Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Anticoncepcionais/farmacologia , Estradiol/análogos & derivados , Regulação da Expressão Gênica/efeitos dos fármacos , Neuropeptídeo Y/metabolismo , alfa-MSH/metabolismo , Análise de Variância , Animais , Núcleo Arqueado do Hipotálamo/citologia , Contagem de Células , Ingestão de Alimentos/efeitos dos fármacos , Estradiol/farmacologia , Feminino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neuropeptídeo Y/genética , Ovariectomia , Ratos , Ratos Wistar , Técnicas Estereotáxicas , Fatores de Tempo , alfa-MSH/genéticaRESUMO
Ivermectin (IVM) is an antiparasitic drug that is widely used in domestic animals. In mammals, IVM acts as a γ-aminobutyric acid (GABA) receptor agonist. This neurotransmitter plays an important role in the regulation of female sexual behavior. The present study investigated the effects of therapeutic (0.2 mg/kg) and high (1.0 mg/kg) IVM doses on female sexual behavior in physiological and pharmacological conditions. Female rats in estrus or treated with estradiol valerate to induce sexual behavior 24 h before the experiments were used. Ivermectin was administered 15 min before the sexual observations. The number of lordosis events in 10 mounts was recorded to calculate the lordosis quotient. The intensity of lordosis (0 [no lordosis], 1 [low lordosis], 2 [normal lordosis] and 3 [exaggerated lordosis]) was scored. In estrus and hormonal treated female rats, both IVM doses decreased the intensity of the lordosis reflex and the percentage of females that presented high levels of lordosis (exaggerated lordosis). However, the number of females that presented lordosis was unaltered. We conclude that in both hormonal conditions, 0.2mg/kg IVM treatment reduced female sexual behavior and the execution of the lordosis reflex. The present results may be useful for avoiding the side effects of this drug in veterinary practice.
Assuntos
Inseticidas/farmacologia , Ivermectina/farmacologia , Comportamento Sexual Animal/efeitos dos fármacos , Animais , Anticoncepcionais/farmacologia , Relação Dose-Resposta a Droga , Estradiol/análogos & derivados , Estradiol/farmacologia , Feminino , Masculino , Ratos , Ratos Wistar , Estatísticas não ParamétricasRESUMO
Previous studies suggested that estrogen plays a role in cognitive function by modulating the cholinergic transmission. However, most of the studies dealing with this subject have been conducted using ovariectomized rats. In the present study we evaluated the effects of physiological and supra-physiological variation of estrogen levels on scopolamine-induced amnesia in gonadally intact female rats. We used the plus-maze discriminative avoidance task (PMDAT) in order to evaluate anxiety levels and motor activity concomitantly to the memory performance. In experiment 1, female Wistar rats in each estrous cycle phase received scopolamine (1 mg/kg) or saline i.p. 20 min before the training session in the PMDAT. In experiment 2, rats in diestrus received estradiol valerate (1 mg/kg) or sesame oil i.m., and scopolamine (1 mg/kg) or saline i.p., 45 min and 20 min before the training, respectively. In experiment 3, rats in diestrus received scopolamine (1 mg/kg) or saline i.p. 20 min before the training, and estradiol valerate (1 mg/kg) or sesame oil i.m. immediately after the training session. In all experiments, a test session was performed 24 h later. The main results showed that: (1) scopolamine impaired retrieval and induced anxiolytic and hyperlocomotor effects in all experiments; (2) this cholinergic antagonist impaired acquisition only in animals in diestrus; (3) acute administration of estradiol valerate prevented the learning impairment induced by scopolamine and (4) interfered with memory consolidation process. The results suggest that endogenous variations in estrogen levels across the estrous cycle modulate some aspects of memory mediated by the cholinergic system. Indeed, specifically in diestrus, a stage with low estrogen levels, the impairment produced by scopolamine on the acquisition was counteracted by exogenous administration of the hormone, whereas the posttraining treatment potentiated the negative effects of scopolamine during the consolidation phase of memory.
Assuntos
Amnésia/induzido quimicamente , Amnésia/metabolismo , Antagonistas Colinérgicos/toxicidade , Estrogênios/metabolismo , Escopolamina/toxicidade , Amnésia/complicações , Análise de Variância , Animais , Ansiedade/etiologia , Aprendizagem da Esquiva/efeitos dos fármacos , Anticoncepcionais/farmacologia , Modelos Animais de Doenças , Estradiol/análogos & derivados , Estradiol/farmacologia , Ciclo Estral/efeitos dos fármacos , Feminino , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Several neurotransmitters, among them neuropeptides, have been implicated in the control of male sexual behavior. Opioids are involved in mediating the positive affective states generated by the execution of sexual behavior in both males and females. We have previously shown that intracerebroventricular administration of endomorphin-1 (EM-1), the specific ligand for the µ opioid receptor, increased the ejaculation latency and interintromission interval and reduced the number of ejaculations during the test. In the present study we evaluated the effect of EM-1 upon male sexual behavior and socio-sexual interactions when infused in the medial preoptic area (MPOA) or the medial amygdala (Me). The results indicate that the administration of EM-1 in the MPOA increased mount and intromission latencies while infusion in the Me increased the number of mounts before ejaculation as well as the ejaculation latency. With respect to socio-sexual interactions, the duration of pursuit was significantly increased after administration of EM-1 in the MPOA. The effects upon sexual behavior and socio-sexual interactions were blocked by administration of the opioid antagonist naloxone. These results indicate that EM-1 modulates the appetitive aspect of sexual behavior in the MPOA and the consummatory phase in the Me.
Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Analgésicos Opioides/farmacologia , Oligopeptídeos/farmacologia , Área Pré-Óptica/efeitos dos fármacos , Comportamento Sexual Animal/efeitos dos fármacos , Comportamento Social , Tonsila do Cerebelo/fisiologia , Animais , Anticoncepcionais/farmacologia , Estradiol/análogos & derivados , Estradiol/farmacologia , Feminino , Masculino , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Ovariectomia , Área Pré-Óptica/fisiologia , Ratos , Ratos Wistar , Estatísticas não ParamétricasRESUMO
UNLABELLED: Prospective cohort study performed to evaluate bone mineral density (BMD) changes up to 12 months postpartum of healthy women and its association with breastfeeding, contraceptive methods, amenorrhea, and body mass index (BMI). There is a trend in bone loss during the first 6 months with posterior recovery, with evidence of a protective effect of hormonal contraception. INTRODUCTION: This study was conducted to evaluate bone mineral density (BMD) changes during postpartum period among healthy women and its association with breastfeeding, use of contraceptive methods, amenorrhea and body mass index (BMI). METHODS: A prospective cohort study including 100 healthy women. Distal BMD was measured 7-10 days, 3, 6, and 12 months postpartum at the nondominant forearm using dual-energy X-ray absorptiometry. Data about breastfeeding duration, amenorrhea, contraceptive use and BMI were collected. RESULTS: Seventy-eight women had a complete set of BMD measurements. The mean duration of exclusive breastfeeding was 125.9 (±66.6) days, with a median total lactation period of 263.5 days. The mean duration of amenorrhea was 164.2 (±119.2) days. BMD measurements showed a significant decrease in the distal radius, however with no significance in the ultradistal radius. When considering only the nonhormonal contraceptive users, the difference at 12 months was significant. Multivariate analysis of variance showed that both BMI and contraceptive use were significantly correlated with BMD. Multiple linear regression analysis showed significant correlation of distal radius with baseline BMD at the same site, pregestational BMI, age, years of schooling and difference in BMI. For ultradistal radius, there was a significant direct correlation with its baseline BMD and pregestational BMI. CONCLUSIONS: There was a trend in bone loss during the first 6 months postpartum with posterior recovery. Also, hormonal contraceptive methods provided protection of bone loss. However, the long duration of breastfeeding and the follow-up were not sufficient to draw definitive conclusions on postweaning BMD conditions.