Male reproductive traits are differentially affected by dietary macronutrient balance but unrelated to adiposity.

Dietary factors influence male reproductive function in both experimental and epidemiological studies. However, there are currently no specific dietary guidelines for male preconception health. Here, we use the Nutritional Geometry framework to examine the effects of dietary macronutrient balance on reproductive traits in C57BL/6 J male mice. Dietary effects are observed in a range of morphological, testicular and spermatozoa traits, although the relative influence of protein, fat, carbohydrate, and their interactions differ depending on the trait being examined. Interestingly, dietary fat has a positive influence on sperm motility and antioxidant capacity, differing to typical high fat diet studies where calorie content is not controlled for. Moreover, body adiposity is not significantly correlated with any of the reproductive traits measured in this study. These results demonstrate the importance of macronutrient balance and calorie intake on reproductive function and support the need to develop specific, targeted, preconception dietary guidelines for males.

Appropriate Systemic Therapy Dosing for Obese Adult Patients With Cancer: ASCO Guideline Update.

PURPOSE: To provide recommendations for appropriate dosing of systemic antineoplastic agents in obese adults with cancer. METHODS: A systematic review of the literature collected evidence regarding dosing of chemotherapy, immunotherapy, and targeted therapies in obese adults with cancer. PubMed and the Cochrane Library were searched for randomized controlled trials, meta-analyses, or cohort studies published from November 1, 2010, through March 27, 2020. ASCO convened an Expert Panel to review the evidence and formulate recommendations. RESULTS: Sixty studies, primarily retrospective, were included in the review. Overall, the evidence supported previous findings that obese adult patients tolerate full, body-size-based dosing of chemotherapy as well as nonobese patients. Fewer studies have addressed the dosing of targeted therapies and immunotherapies in relation to safety and efficacy in obese patients. RECOMMENDATIONS: The Panel continues to recommend that full, weight-based cytotoxic chemotherapy doses be used to treat obese adults with cancer. New to this version of the guideline, the Panel also recommends that full, approved doses of immunotherapy and targeted therapies be offered to obese adults with cancer. In the event of toxicity, the consensus of the Panel is that dose modifications of systemic antineoplastic therapies should be handled similarly for obese and nonobese patients. Important areas for future research include the impact of sarcopenia and other measures of body composition on optimal antineoplastic dosing, and more customized dosing based on pharmacokinetic or pharmacogenetic factors.Additional information is available at www.asco.org/supportive-care-guidelines.

Exogenous melatonin advances the ram breeding season and increases testicular function.

Governed by melatonin, ovine reproductive seasonality limits production outcomes due to periods of decreased reproductive efficiency. Though it is established that slow-release melatonin implants improve out of season reproductive performance in the ewe, the comprehensive effects of exogenous melatonin in the ram remain inconclusive. This study aimed to ultimately clarify the ability of exogenous melatonin to alter ram reproductive function during the non-breeding season and the subsequent breeding season. Hence, we investigated the effect of exogenous melatonin on reproductive endocrinology, semen quality and production, testicular size and libido in Merino and Poll Dorset rams (n = 31, using a subset of 18 rams for analysis of semen production and quality). Melatonin treatment resulted in elevation of melatonin in seminal plasma from 1-8 weeks post-implantation and in blood plasma at 6 weeks post-implantation. The blood plasma testosterone of implanted rams was greater than controls at both 6 weeks post-implantation and during the following breeding season. Implanted rams exhibited increased testicular size and number of sperm per ejaculate from 3-12 weeks post-implantation but did not demonstrate any change in sperm motility or morphology in response to treatment. Compared to their control counterparts, melatonin-treated Poll Dorset rams exhibited a lower percentage of sperm DNA fragmentation during several weeks of the non-breeding season. Though melatonin increased the likelihood of ejaculate collection in Poll Dorset rams (P < 0.05), libido was otherwise unaffected by treatment. Melatonin did not alter seminal plasma concentrations of inhibin A or Anti-Mullerian hormone, however, for the first time in the ram we have shown Anti-Mullerian hormone to be positively correlated with the number of sperm per ejaculate and sperm motility (r = 0.464 and 0.3242 respectively, P < 0.001), and inhibin A to be correlated to the number of sperm per ejaculate (r = 0.1786, P = 0.0135). These results indicate that melatonin is able to both systemically upregulate reproduction and act directly upon testicular function in the ram.

Obesity significantly alters the human sperm proteome, with potential implications for fertility.

PURPOSE: In men, obesity may lead to poor semen parameters and reduced fertility. However, the causative links between obesity and male infertility are not totally clear, particularly on a molecular level. As such, we investigated how obesity modifies the human sperm proteome, to elucidate any important implications for fertility. METHODS: Sperm protein lysates from 5 men per treatment, classified as a healthy weight (body mass index (BMI) ≤ 25 kg/m2) or obese (BMI ≥ 30 kg/m2), were FASP digested, submitted to liquid chromatography tandem mass spectrometry, and compared by label-free quantification. Findings were confirmed for several proteins by qualitative immunofluorescence and a quantitative protein immunoassay. RESULTS: A total of 2034 proteins were confidently identified, with 24 proteins being significantly (p < 0.05) less abundant (fold change < 0.05) in the spermatozoa of obese men and 3 being more abundant (fold change > 1.5) compared with healthy weight controls. Proteins with altered abundance were involved in a variety of biological processes, including oxidative stress (GSS, NDUFS2, JAGN1, USP14, ADH5), inflammation (SUGT1, LTA4H), translation (EIF3F, EIF4A2, CSNK1G1), DNA damage repair (UBEA4), and sperm function (NAPA, RNPEP, BANF2). CONCLUSION: These results suggest that oxidative stress and inflammation are closely tied to reproductive dysfunction in obese men. These processes likely impact protein translation and folding during spermatogenesis, leading to poor sperm function and subfertility. The observation of these changes in obese men with no overt andrological diagnosis further suggests that traditional clinical semen assessments fail to detect important biochemical changes in spermatozoa which may compromise fertility.

Cryopreservation and egg yolk medium alter the proteome of ram spermatozoa.

Cryopreservation causes significant lethal and sub-lethal damage to spermatozoa. In order to improve freezing outcomes, a comprehensive understanding of sub-lethal damage is required. Cryopreservation induced changes to sperm proteins have been investigated in several species, but few have employed currently available state of the art, data independent acquisition mass spectrometry (MS) methods. We used the SWATH LC-MS method to quantitatively profile proteomic changes to ram spermatozoa following exposure to egg yolk and cryopreservation. Egg yolk contributed 15 proteins to spermatozoa, including vitellogenins, apolipoproteins and complement component C3. Cryopreservation significantly altered the abundance of 51 proteins. Overall, 27 proteins increased (e.g. SERPINB1, FER) and 24 proteins decreased (e.g. CCT subunits, CSNK1G2, TOM1L1) in frozen thawed ram spermatozoa, compared to fresh spermatozoa. Chaperones constituted 20% of the proteins lost from spermatozoa following cryopreservation. These alterations may interfere with both normal cellular functioning and the ability of frozen thawed spermatozoa to appropriately respond to stress. This is the first study to apply SWATH mass spectrometry techniques to characterise proteins contributed by egg yolk based freezing media and to profile cryopreservation induced proteomic changes to ram spermatozoa. SIGNIFICANCE: This study profiles changes to the sperm proteome induced by exposure to egg yolk based media and the process of cryopreservation, and the biological consequences are discussed.

Seminal plasma aids the survival and cervical transit of epididymal ram spermatozoa.

Seminal plasma purportedly plays a critical role in reproduction, but epididymal spermatozoa are capable of fertilisation following deposition in the uterus, calling into question the biological requirement of this substance. Through a combination of direct observation of spermatozoa in utero using probe-based Confocal Laser Endomicroscopy, in vivo assessment of sperm fertility and in vitro analysis of various sperm functional parameters, this study investigated the role of seminal plasma in spermatozoa transit through the cervix of the ewe. Following deposition in the cervical os, epididymal spermatozoa previously exposed to seminal plasma displayed an enhanced ability to traverse the cervix as evidenced by both significantly higher pregnancy rates and numbers of spermatozoa observed at the utero-tubal junction when compared with epididymal spermatozoa not previously exposed to seminal plasma. The beneficial effect of seminal plasma on sperm transport was clearly localised to transit through the cervix as pregnancy rates of spermatozoa deposited directly into the uterus were unaffected by exposure to seminal plasma. This phenomenon was not explained by changes to sperm motion characteristics, as seminal plasma had no effect on the motility, kinematic parameters or mitochondrial membrane potential of spermatozoa. Rather, in vitro testing revealed that seminal plasma improved the ability of epididymal spermatozoa to penetrate cervical mucus recovered from ewes in oestrus. These results demonstrate that the survival and transport of ram spermatozoa through the cervix of the ewe is not linked to their motility or velocity but rather the presence of some cervical penetration trait conferred by exposure to seminal plasma.

Adjuvant endocrine therapy initiation and persistence in a diverse sample of patients with breast cancer.

Adjuvant endocrine therapy for breast cancer reduces recurrence and improves survival rates. Many patients never start treatment or discontinue prematurely. A better understanding of factors associated with endocrine therapy initiation and persistence could inform practitioners how to support patients. We analyzed data from a longitudinal study of 2,268 women diagnosed with breast cancer and reported to the Metropolitan Detroit and Los Angeles SEER cancer registries in 2005-2007. Patients were surveyed approximately both 9 months and 4 years after diagnosis. At the 4-year mark, patients were asked if they had initiated endocrine therapy, terminated therapy, or were currently taking therapy (defined as persistence). Multivariable logistic regression models examined factors associated with initiation and persistence. Of the 743 patients eligible for endocrine therapy, 80 (10.8 %) never initiated therapy, 112 (15.1 %) started therapy but discontinued prematurely, and 551 (74.2 %) continued use at the second time point. Compared with whites, Latinas (OR 2.80, 95 % CI 1.08-7.23) and black women (OR 3.63, 95 % CI 1.22-10.78) were more likely to initiate therapy. Other factors associated with initiation included worry about recurrence (OR 3.54, 95 % CI 1.31-9.56) and inadequate information about side effects (OR 0.24, 95 % CI 0.10-0.55). Factors associated with persistence included two or more medications taken weekly (OR 4.19, 95 % CI 2.28-7.68) and increased age (OR 0.98, 95 % CI 0.95-0.99). Enhanced patient education about potential side effects and the effectiveness of adjuvant endocrine therapy in improving outcomes may improve initiation and persistence rates and optimize breast cancer survival.

The influence of non-clinical patient factors on medical oncologists' decisions to recommend breast cancer adjuvant chemotherapy.

The extent to which medical oncologists consider non-clinical patient factors when deciding to recommend adjuvant chemotherapy is unknown. Medical oncologists who treated a population-based sample of early stage breast cancer patients reported to the Los Angeles and Detroit Surveillance, Epidemiology, and End Results registries 2005-2007 were asked how strongly they consider a patient's ability to follow instructions, level of social support, and level of work support/flexibility in decisions to recommend adjuvant chemotherapy. Responses of 4 (Quite strongly) or 5 (Very strongly) on a five-point Likert scale defined strong consideration. Associations between oncologist/practice characteristics and strong consideration of each non-clinical factor were examined. 134 oncologists (66 %) reported strong consideration of one or more factor. Ability to follow instructions was strongly considered by 120 oncologists (59 %), social support by 78 (38 %), and work support/flexibility by 73 (36 %). Larger percent of practice devoted to breast cancer was associated with lower likelihood of strongly considering ability to follow instructions [odds ratio (OR) 0.98, 95 % confidence interval (CI) 0.97-0.99; P = 0.04]. Increased years in practice was associated with lower likelihood of strongly considering social support (OR 0.96, CI 0.93-0.99; P = 0.011), while non-white race (OR 2.1, CI 1.03-4.26; P = 0.041) and tumor board access (OR 2.04, CI 1.01-4.12; P = 0.048) were associated with higher likelihood. Non-white race was associated with strongly considering work support/flexibility (OR 2.44, CI 1.21-4.92; P = 0.013). Tumor board access (OR 2, CI 1.00-4.02; P = 0.051) was borderline significant. Non-clinical patient factors play a role in medical oncologist decision-making for breast cancer adjuvant chemotherapy recommendations.

Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline.

PURPOSE: To provide recommendations for appropriate cytotoxic chemotherapy dosing for obese adult patients with cancer. METHODS: The American Society of Clinical Oncology convened a Panel of experts in medical and gynecologic oncology, clinical pharmacology, pharmacokinetics and pharmacogenetics, and biostatistics and a patient representative. MEDLINE searches identified studies published in English between 1996 and 2010, and a systematic review of the literature was conducted. A majority of studies involved breast, ovarian, colon, and lung cancers. This guideline does not address dosing for novel targeted agents. RESULTS: Practice pattern studies demonstrate that up to 40% of obese patients receive limited chemotherapy doses that are not based on actual body weight. Concerns about toxicity or overdosing in obese patients with cancer, based on the use of actual body weight, are unfounded. RECOMMENDATIONS: The Panel recommends that full weight-based cytotoxic chemotherapy doses be used to treat obese patients with cancer, particularly when the goal of treatment is cure. There is no evidence that short- or long-term toxicity is increased among obese patients receiving full weight-based doses. Most data indicate that myelosuppression is the same or less pronounced among the obese than the non-obese who are administered full weight-based doses. Clinicians should respond to all treatment-related toxicities in obese patients in the same ways they do for non-obese patients. The use of fixed-dose chemotherapy is rarely justified, but the Panel does recommend fixed dosing for a few select agents. The Panel recommends further research into the role of pharmacokinetics and pharmacogenetics to guide appropriate dosing of obese patients with cancer.