Several organ systems can be affected by nicotine/cigarette smoking (CS); however, there is a gap of knowledge about the role of local neurotransmitter system, brain-derived neurotrophic factor (BDNF), and dopamine (DA) in testicular toxicity. Therefore, the aim of the present study is to explore the toxic impact of short-and long-term exposure to oral nicotine and passive CS on adult albino Wistar rats, using doses that closely mimic the human smoking scenario. Our results showed dose-and time-dependent loss of developing spermatogonia and spermatocyte of the seminiferous tubules, disruption of basement membrane, DNA damage, and high serum cotinine upon exposure to nicotine and CS, resulting in low sperm count as compared to control. Further, the results showed the upregulation of BDNF, DA, tyrosine hydroxylase (TH), and pro-oxidants, ie, reactive oxygen species (ROS) and inducible nitric oxide synthetase (iNOS), in the exposed testis and downregulation of the antioxidants such as, ascorbate and Nrf2 when compared with the control. Thus, our results for the first time highlight a potential role of the local neurotransmitter system and antioxidant depletion (Nrf2) in nicotine/CS-induced testicular pathogenesis, which could underpin the development of therapeutic interventions targeted at oxidative stress-associated disorders, and probably establish a link with the brain system contributing to addiction.
Case presentation of a healthy G2P2 patient in her late 30s, treated with in vitro fertilization–intracytoplasmic sperm injection for severe male factor infertility. The patient was treated with a gonadotropin-releasing hormone antagonist cycle (GnRH-An). GnRH-An (Cetrorelix) daily injections were started on cycle day 7 and switched to a different GnRH-An preparation (Ganirelix) due to an allergic reaction. Serum hormone levels and ultrasound monitoring were uneventful until day 13, when a corpus luteum cyst was detected, in addition to multiple intact follicles. Serum progesterone increased to 45 nmol/L, while serum luteinizing hormone (LH) remained low. Thirty-six hours following a day 13 human chorionic gonadotropin (HCG) triggering, 18 cumulus-oocyte complexes were successfully retrieved, resulting in the development of two blastocysts. This is an example for an isolated single-follicle ovulation without compromising the rest of the cohort. A possible explanation is an increased concentration of LH receptors on a specific follicle or increased sensitivity to endogenous GnRH in GnRH-An cycles. Clinicians facing a similar scenario should consider not cancelling the cycle in case additional intact follicles are present.
Dipeptidyl peptidase is a highly glycosylated serine protease with a broad tissue distribution. In the present study, we investigated the alteration of the activity of dipeptidyl peptidase of spermatozoa at different maturational levels in rat epididymis and the apparent correlation of enzyme activity with sperm forward motility. The maximum activity of the enzyme was observed in spermatozoa from the corpus or middle part of the epididymis. This glycyl-proline ρ-nitroanilide hydrolyzing enzyme of epididymal spermatozoa showed significant similarities with biochemical properties of dipeptidyl peptidase (DPP) type IV. Sitagliptin, a specific inhibitor of DPPIV, leads to a more effective and complete inhibition of the peptidase in spermatozoa collected from different parts of epididymis. The complete inhibition by Hg2+ and partial insensitivity toward Cd2+ also confirmed the similarities with ion sensitivity of DPPIV. Treatment of mature cauda spermatozoa with sitagliptin (1 mM) showed a significant inhibition in forward thrust in motility. This result suggests that sperm forward motility may be regulated by DPPIV-like enzyme of maturing epididymal spermatozoa.
Antioxidant therapy is thought to improve oocyte quality through the reduction of oxidative stress. Melatonin and coenzyme Q10 (CoQ10) are known antioxidants. We aimed to investigate the clinical efficacy of exogenous melatonin supplementation with or without CoQ10 in improving oocyte quantity and quality. Fifty- three women undergoing cycles at Monash IVF were supplemented with melatonin 4 mg daily, with 19 of those additionally supplemented with 150 mg of CoQ10. Controls were matched at a 2: 1 ratio to cases. Data were taken from an index (pretherapy) cycle and from a therapeutic (posttherapy) cycle for both cases and controls. Comparisons were made directly between cases and controls in the therapeutic cycle and by comparing the median differences of the change in outcomes from the index to therapeutic cycle. Primary outcomes included follicle, oocyte, and metaphase II oocytes (MII) counts. Results showed higher median absolute oocyte numbers (6.00 vs. 4.00, P = 0.049) in the case group. Cases and controls were significantly different when comparing median change between cycles in oocyte number (0.00 vs. - 1.00, P = 0.028) and MII count (0.00 vs. - 1.00, P = 0.034). However, this was the result of poorer outcomes in the control group rather than improvements in the case group, and it cannot be concluded that treatment improved oocyte quality.
OBJECTIVE:To compare the effects of different protocols of controlled ovarian hyperstimulation on thyroid function with those of the natural menstrual cycle.STUDY DESIGN: Prospective controlled study.SETTING: University Medical Center.PATIENTS: A total of 97 women without a history of endocrine disease undergoing intrauterine insemination either in a natural cycle, or with mild ovarian hyperstimulation, or in vitro fertilization (IVF).MAIN OUTCOME MEASURES: estradiol (E 2 ), thyroxine binding globulin (TBG), free thyroxine (FT 4 ), total thyroxine (TT 4 ) and thyroid stimulating hormone (TSH) during the midluteal phase.RESULTS: In the IVF group midluteal E 2 , TBG, and TT 4 were significantly higher; midluteal FT 4 was significantly lower (mean difference: -1.46 pmol/L; P 0.001) and midluteal TSH was significantly higher (mean difference: 0.52 mU/L; P = 0.015).CONCLUSIONS: Ovarian hyperstimulation in IVF is associated with lower midluteal FT 4 and higher midluteal TSH levels compared to the natural cycle.
The use of exogenous gonadotropins to increase oocyte yields for better pregnancy outcomes remains unpredictable and inefficient. The objectives of this review are to address two questions concerning this issue: (1) are there any alternatives for improving consistency in oocyte yields? (2) is it possible to develop a molecular diagnostic test for oocytes with blastocyst potential? Studies in sheep with a heterozygous inactivating mutation in the oocyte-derived growth factor, bone morphogenetic protein 15 (BMP15), report increased oocyte yields and significantly more offspring. Moreover, partial immuno-neutralization of BMP15 bioactivity increases oocyte yield without modifying gonadotropin or ovarian steroid secretion. Therefore, it is hypothesized that the development of BMP15 antagonists may prove them to be suitable alternatives to exogenous gonadotropins. Recent evidence from analyses of candidate gene expression in human cumulus cells separated from individual oocytes before IVF indicates a potential non-invasive molecular screen for oocytes with improved blastocyst and live-birth outcomes.
Immunobiological changes in spermatozoa within the male reproductive tract are vital for their viability, and hence for reproductive efficiency. The secretions of the seminal vesicles have immunosuppressive property that attenuates the antigenic effects of spermatozoa in the male reproductive tract. However, when spermatozoa find a way to outside of the rete testis or epididymis due to trauma or infection, they can cause significant inflammatory and immunological reactions in the surrounding tissues. This has also been observed in the female reproductive tract. However, such cases are rare and the reason for this is unknown. Antisperm antibodies are the main cause of infertility in humans. The purpose of this review is to analyze these immunobiological changes from the time of spermatozoa formation in rete testis to their role in fertilizing the oocytes in the female reproductive tract.
Despite continuing significant research efforts and an increasing prevalence of preterm labor (PTL) worldwide, a comprehensive understanding of the mechanisms involved remains to be established; such is the complexity of the interactions involved. Closing the knowledge gaps in this field would afford an opportunity to improve mortality and morbidity rates on a global scale. Early identification of pregnancies at risk of PTL would increase the possibility of delaying birth (where appropriate) prior to initiation of labor. This requires identification of appropriate biomarkers that are readily detectable in easily obtained clinical samples. A family of arachidonic acid metabolites, called eicosanoids. Eicosanoids have shown promise as possible diagnostic biomarkers for PTL. The inherent problems of antibody cross-reactivity in immunoassay methods has, however, resulted in possible misinterpretation of past results. The following mini-review outlines the necessity of such diagnostic targets and the problem with previous research methods and also summarizes recent findings in the field.
The evolution of the large and complex brain was a big advantage to early humans in their social interactions and encounters with unfamiliar habitats. But it was not without a high cost to women’s sexual and reproductive health. The developing fetal brain needs and consumes a lot of energy. To meet this need, a more intensely invasive placenta evolved and with it, the risk of excessive bleeding when the placenta separates partially or completely from the uterine wall, a major cause of maternal death. Delivering the large fetal head is an obstetric dilemma, particularly with the relatively narrow and irregular bipedal pelvis. The additional long time needed for the postnatal growth of the brain dictated the necessity for continued paternal investment. To strengthen the pair bond, sex was completely dissociated from reproduction and ovulation was concealed. However women then became vulnerable to sexual violence, sexually transmitted infections, and unwanted pregnancy. Recently, the human brain has been repaying women in the currency of modern science, including making motherhood safer and developing women-controlled contraceptive technologies. Scientific challenges still stand. For example, the modern woman has to cope with the burden of a reproductive system evolved for a hunter gatherer. Women have already fulfilled the divine obligation to replenish the earth, and it is time for science to help women to finally emerge from behind the mother.
Study Objective: Chemical protection against cisplatin, which is a commonly used cancer chemotherapeutic agent, is not well defined. We tested the hypothesis that the antioxidant mesna might protect against the cisplatin-induced repoductive effects in female rats. Design & Setting: Adult female rats were injected with saline, cisplatin alone, or mesna + cisplatin, mated with males, and euthanized on gestational day 17. Patients: Animal Model. Interventions: The administration of either cisplatin or mesna + cisplatin (two injections one week apart, mesna 30 minute pretreatment) followed by mating one week after treatment. Main Outcomes Measured: The number corpora lutea, implantation and resorptions sites, viable and non-viable fetuses, fetal weights, and the level of progesterone per corpus luteum. Results: The administration of cisplatin caused an increase in pre- and post- implantation loss, an increase in the number of resorptions and a decrease in the number of viable fetuses. Mesna administered prior to cisplatin resulted in a decrease in the rate of the pre- and post implantation loss, along with a decrease in the number of resorptions and an increase in the number of live fetuses. Conclusions: Prior exposure to cisplatin caused significant adverse effects on fertility as evidenced by the decreased implantation due to increased fetal loss. The administration of mesna appeared to temper cisplatin damage by lessening the cisplatin effects on fetal resorption.
Objective: The present study was performed to evaluate whether the hormone profiles of the mid-luteal phase impact on the chances of conceiving during the following menstrual cycle in connection with intrauterine insemination (IUI) treatment. Design: Observational clinical study. Setting: Infertility clinic. Patient(s): 92 women underwent a total of 288 IUI treatment cycles, without use of exogenous hormones. Intervention(s): The mid-luteal hormone profiles including levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, oestradiol, progesterone, androstenedione and testosterone, were measured in the preceding cycle of IUI treatment. Main outcome measure(s): The mid-luteal hormone profiles were correlated to whether the women conceived in the following natural menstrual cycle in which IUI treatment was performed and to whether ovulation occurred on the same ovary in two consecutive cycles (ipsilateral ovulation) or jumped from one ovary to the other (contralateral ovulation). Result(s): When ovulation occurred from the same ovary in two consecutive cycles mid-luteal levels of progesterone of the preceeding cycle were significantly lower in conceptional than non-conceptional cycles. No significant differences of LH, FSH, estradiol, androstendione and testosterone were observed when correlating the different parameters. Conclusion(s): Lower mid-luteal progesterone levels seem to enhance chances of conception when ovulation occurs in the same ovary for two consecutive cycles.
Follicle-stimulating hormone, both naturally synthesized and as commercial preparations, exists as different isoforms. Variation in the process of glycosylation, particularly in the number of terminal sialic-acid residues, gives rise to isoforms of varying acidic profiles with differences in half-life and bioactivity. Based on the known follicle-stimulating hormone isoform variation across the reproductive cycle, it is possible that the follicle-stimulating hormone isoform profile used in controlled ovarian stimulation may impact follicular recruitment and clinical treatment outcomes. In light of the uncertainty regarding the clinical relevance of follicle-stimulating hormone isoforms in fertility treatment, published studies exploring this topic are reviewed.
Objective: To determine the relationship between ovarian cortical tissue dimensions and the growth and survival of human primordial follicles in vitro. Design: Human study. Setting: Research laboratory of university hospital. Patient(s): Women undergoing benign gynaecological procedures. Intervention(s): Fresh ovarian cortical tissues were removed and cut into 32 smaller pieces of various sizes/shapes and 22 were cultured in serum-free medium for 7 days. Main outcome measure(s): Follicle viability, density and growth potential assessed by histology. Result(s): Strong correlations were observed between the density-weighted shape descriptor and the reciprocals of viability and growth ratio. Conclusion(s): The correlation between follicular surface area and viability/development suggests the use of the smallest practical size as the most efficient way to maximise follicular viability and growth potential. Our mathematical model may also provide an analytical technique for future research relating to in vitro tissue culture.
There has been an astounding explosion in the number of clinics offering ART techniques- 426 program in the US and 600 in Europe. Despite enormous advances regarding the technical aspects of the IVF procedure, the parents’ contribution has virtually been ignored. What is reassuring for patients is that lifestyle habits are within the patient’s control, and when modified, could lead to healthy babies. The focus of this paper will be on the current state of knowledge about the effects of female and male caffeine and alcohol use, and psychological stress on the reproductive endpoints of IVF. There is currently only one study on the effects of caffeine on IVF. In this study, caffeine intake by women had a profound effect on: 1) Miscarriages, 2) Not achieving a live birth and 3) Infant gestational age. The findings of this study require further confirmation. Success rates may be further affected by alcohol consumption. Female alcohol use was associated with: 1) A decrease in number of oocytes aspirated, 2) Not achieving a pregnancy, and 3) Increased risk of miscarriage. Male alcohol use was associated with: 1) Spontaneous miscarriages, and 2) Not achieving a live birth, particularly if consuming beer. Stress also has an impact on IVF success rates. There are several statistically significant studies on baseline and procedural depression, anxiety, stress, and mood, as well as stress hormones that all negatively affected pregnancy rates after IVF. However, the literature on stress and ART was devoid of an instrument that captures the female and male experience of going through ART. Thus, an instrument was developed that rated concern levels about anesthesia, surgery, pain, recovery time, side-effects, finances, missing work, insufficient information and delivering a healthy baby. At baseline, women who were concerned about the medical aspects of the procedure had fewer oocytes retrieved and fertilized. For women concerned about missing work, they had over twice the risk of not achieving a pregnancy, while women extremely concerned about finances had a very high risk of no live birth. Understanding both the independent and combined effects of stress, alcohol, and caffeine on ART may ultimately lead to effective interventions that will decrease adverse outcomes and in turn, produce healthy babies that mature into healthy children and adults.
A strong body of evidence indicates that the negative effect of cigarette smoking on fertility comprises fairly every system involved in the reproductive process. The impact of cigarette smoking on ovarian reserve is clearly evidenced by younger age at menopause of smokers. Tobacco compounds’ impairment of the process of ovarian follicle maturation is expressed by worse in-vitro fertilization parameters in cycles performed on women with smoking habits. Also, uterine receptiveness and tubal function are significantly altered by the smoking habit. In men, cigarette smoking reduces sperm production, increases oxidative stress, and DNA damage. Spermatozoa from smokers have reduced fertilizing capacity, and embryos display lower implantation rates. Couples at reproductive age should be strongly discouraged to smoke.
This presentation deals with three different and diverse subject areas which may have effects on the reproductive potential of an individual. Pollutants or environmental contaminants are compounds or chemicals which may be persistent and ubiquitous, sedentarism which is related to lifestyle and circadian rhythm which is inherent in tissues, organs or whole body.
Trophectoderm formation is the first cell lineage segregation during early embryo development. Further differentiation of trophectoderm to various types of trophoblasts is the key event of placentation process, which is crucial for embryonic implantation and successful pregnancy. The anatomic structure of human placenta is different from that of rodents which have provided the best model to study molecular and cellular mechanisms of trophoblast development. However, due to ethical and practical restrictions, the regulatory mechanisms of human trophoblast development are poorly explored and understood. Recent evidences demonstrate that human embryonic stem cells (ESCs) are capable of differentiation towards trophoblasts in culture, after induction by extracellular signals or specific genetic manipulation of master regulatory factors. This review summarizes recent advances in deriving human trophoblasts from human ESCs, and suggests novel mechanisms that regulate the human trophectoderm commitment.
In humans there is evidence that in utero exposure to cigarette smoke results in decreased fertility in female offspring. We have demonstrated in rats that fetal and neonatal exposure to nicotine alone results in impaired fertility and increased follicular atresia in the adult female offspring. In mammals, the insulin-like growth factor-I and -II (IGF-I and -II) and their binding proteins (IGFBPs) are considered stimulators and inhibitors of follicular growth and maturation. Therefore we hypothesized that dysregulation of the intra-ovarian IGF system could be implicated in the impaired fertility observed in nicotine-exposed offspring. Nulliparous female Wistar rats were exposed to nicotine (1 mg/kg/d) for 2 weeks prior to mating until weaning. Ovaries were collected on the morning of estrus from sexually mature saline- and nicotine-exposed offspring. Protein expression of IGF ligands and receptors (IGFR-I and IGFR-II) were quantified by western blot and immunohistochemistry. The expression of IGF-I, IGF-II; IGFR-I, IGFR-II; and IGFBP1–6 mRNA in the ovary was deter- mined by semi-quantitative reverse transcriptase-PCR. Results showed that nicotine exposure significantly reduced IGF-I, IGF-II and IGFR-I protein expression (p < 0.01) relative to saline controls. Furthermore, nicotine-exposed offspring had significantly reduced IGFR-II mRNA expression (p < 0.01) in the ovary. Data from this study suggest that the decreased fertility and increased follicular atresia in nicotine-exposed animals may be due, in part, to disruption of IGF regulation in the ovary.
Obesity presents an increasing prevalence in developed countries and impairs human reproduction in both natural and assisted conception cycles. A healthy liveborn is less probable among obese women due to a combination of lower implantation and pregnancy rates, higher preclinical and clinical miscarriage rates and more frequent complications during pregnancy for both mother and fetus. Gametes, embryos and uterus seem to be negatively affected by the abnormal hormonal and metabolic environment present in obese men and women. Lifestyle therapy for weight reduction based on hypocaloric diet and exercise is the best approach for improving the reproductive performance of these patients. Pharmacotherapy does not seem to be useful and bariatric surgery indicated only for fertility purposes is currently considered a risky and understudied procedure.
