Contreras, P. H., Serrano, F. G., Salgado, A. M., & Vigil, P. (2018). Insulin Sensitivity and Testicular Function in a Cohort of Adult Males Suspected of Being Insulin-Resistant. Frontiers in medicine, 5, 190. https://doi.org/10.3389/fmed.2018.00190
Contreras PH, Serrano FG, Salgado AM, Vigil P. Insulin Sensitivity and Testicular Function in a Cohort of Adult Males Suspected of Being Insulin-Resistant. Front Med (Lausanne). 2018;5:190. doi:10.3389/fmed.2018.00190
Contreras, P. H., et al. "Insulin Sensitivity and Testicular Function in a Cohort of Adult Males Suspected of Being Insulin-Resistant." Frontiers in medicine, vol. 5, 2018, pp. 190.
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Biomedical Division, Reproductive Health Research Institute (RHRI), Santiago, Chile
Insulin-resistant men had about twice the rate of low testosterone
Men with insulin resistance were about twice as likely to have low testosterone, a study of 141 men suspected of insulin resistance found. In this group, low testosterone occurred in about 32 of 100 insulin-resistant men and 15 of 100 men without it. Waist size flagged insulin resistance well in these men. It flagged low testosterone less well.
Key Findings
Among 141 men aged 18 to 80, 94 (66.66%) were insulin resistant and 37 (26.24%) had hypogonadism (low testosterone).
Low testosterone occurred in 30 of 94 insulin-resistant men (31.91%) and 7 of 47 men without insulin resistance (14.89%), a relative risk of 2.143.
Of the 37 men with low testosterone, 30 (81.08%) were also insulin resistant.
A waist over 99 cm predicted insulin resistance (AUROC 0.812); 89.74% of those men had it. A waist over 110 cm was a mediocre predictor of low testosterone (AUROC 0.640).
Normal weight did not rule out insulin resistance: 8 of the 15 normal-weight men (53.3%) had it. Among 66 obese men, 9 (13.6%) were not insulin resistant.
Interpretation
Each man had one insulin test and one testosterone blood draw, so the design shows association only. The men were chosen because clinicians already suspected insulin resistance, so the rates describe this selected group. They do not describe men in general. Testicular function meant testosterone and sex hormone-binding globulin. Sperm and fertility were not measured. AUROC rates how well a measure separates two groups, from 0.5 (chance) to 1 (perfect). The authors suggest abdominal obesity brings insulin resistance first and low testosterone years later, a sequence one measurement cannot test. They did not measure leptin, a possible link they raise only as speculation.
RRM Context
Restorative reproductive medicine looks for root causes in both partners. Male factor contributes to many couples' infertility. Here, insulin resistance and low testosterone clustered in the same men, and normal weight did not exclude insulin resistance. The study reports no semen results or pregnancies.
Our editorial summary of this paper, not the article's abstract.
Abstract
A cohort of 141 males (18-80 yo, 42.9 ± 12.9) strongly suspected of being Insulin Resistant (IR) was prospectively studied by determining their insulin sensitivity (Pancreatic Suppression Test, PST) and testicular function (total testosterone and SHBG). The subjects were labeled as IR when the Steady State Plasma Glucose (SSPG) was ≥150 mg/dL and Non-Insulin Resistant (NIR) when SSPG was <150 mg/dl; similarly, the subjects were labeled as Hypogonadal (HYPOG) when total testosterone was ≤3.0 ng/mL and Eugonadal (EUG) when total testosterone was >3.0 ng/mL. Two out of three subjects turned out to be IR, while around one in four subjects were HYPOG. Contingency analysis indicated a significant interdependence between insulin resistance and hypogonadism (chi-square was 4.69, p = 0.0303). Age (>43 yo) predicted hypogonadism (AUROC 0.606, p = 0.0308). Twice as many HYPOG subjects were IR as compared with EUG subjects. Also, HYPOG subjects exhibited higher SSPG values as compared with EUG subjects. Statistically, neither Weight nor BMI predicted hypogonadism, while Waist Circumference (>110 cm) was only a mediocre predictor (AUROC 0.640, p = 0.009). SSPG (>224 mg/dL) on the other hand, was the best predictor of hypogonadism (AUROC 0.709, p = 0.002), outperforming Waist Circumference (half of the subjects with an SSPG >224 mg/dL were HYPOG). Age did not predict insulin resistance, while Weight (>99 kg), BMI (>29), and especially, Waist Circumference (>99 cm, AUROC 0.812, p < 0.0001) were all predictors of insulin resistance. Almost 90% of the subjects with a waist circumference >99 cm was IR. As a logical consequence of the selection criteria (various clues suggesting insulin resistance), most subjects with normal weight in this cohort were IR (53.3%) while 20% were HYPOG. On the other hand, 13.6% of the obese subjects were NIR, and 2 out of 3 of them were both NIR and EUG. In conclusion, Waist Circumference predicted both insulin resistance (>99 cm) and hypogonadism (>110 cm), suggesting that the first hit of abdominal obesity is insulin resistance and the second hit is male hypogonadism. Normal weight did not protect from IR, while a relevant proportion of obese subjects were NIR (with 2/3 being also EUG).
Progesterone supplementation reverses 83% of transcript changes in the secretory endometrium induced by postovulatory mifepristone, potentially mitigating its antiprogestogenic effects. Mifepristone (RU486) antagonizes progesterone signaling in human endometrium interfering in the secretory phenotype after estradiol priming. The objective of the present study was to determine effect in the endometrial transcript profile of progesterone supplementation after the administration of 200 mg of the antiprogestin mifepristone 48 h after the LH peak (LH+2, LH+0 = LH peak). Endometrial samples were obtained on LH+7 after vaginal administration of micronized progesterone 200 mg/day for 3 days in nine women of proven fertility, each one contributing with one cycle treated with progesterone and another with a placebo. In addition, endometrial samples were obtained in LH+7 from a subgroup of four women with no administration of mifepristone, with each one contributing with one cycle treated with vaginal progesterone supplementation or placebo as a reference. RNA-seq was used to identify transcripts significantly regulated under the administration of progesterone vs placebo with or without postovulatory mifepristone. We observed that 713 transcripts changed significantly in the endometrium under mifepristone after progesterone supplementation in group A. Of these, progesterone reversed approximately 83% of the transcripts affected by mifepristone in the secretory endometrium. Bioinformatic analyses revealed that these transcripts were enriched in genes associated with mitochondrial function, particularly oxidative phosphorylation. In addition, NR2C2 and DLX1 were identified as potential transcription factors that may mediate the effects of progesterone in the endometrium. We conclude that progesterone supplementation after postovulatory mifepristone administration can reverse the antiprogestogenic effects for most of the affected endometrial transcripts.
Del Río JP et al., 2024·Front Psychol·Free full text on PubMed Central
Hormones produced by the hypothalamic-pituitary-adrenal-gonadal (HPAG) axis are crucial for modulating central nervous system (CNS) function and development throughout a person's life. Disruptions in HPAG function can impact psychological development, particularly during adolescence-a period marked by psychological growth and the maturation of the HPAG axis. An early indicator of HPAG alterations is ovulatory dysfunction (OD), a common condition among adolescents. This study explored the associations between neuroactive hormones and personal growth in adolescents with OD. Female participants aged 12-25 years with OD were recruited, and assessments were conducted to profile their basic hormonal levels and various dimensions of individual development, including self-concept clarity, sense of coherence, self-esteem, perfectionism, self-control, and mood states. Adolescents with OD (n = 117) had lower self-concept clarity and self-esteem compared to reference data. A significant portion of the sample displayed elevated levels of tension (71.25%), confusion (62.5%), fatigue (58.22%), and depression (52.6%). Self-esteem scores were negatively correlated with DHEAS (r = -0.224; p = 0.026) and glucose (r = -0.249; p = 0.010). Higher levels of free testosterone were associated with increased depression scores (coef = 0.2398; p = 0.002), whereas higher estradiol levels were linked to lower aggressiveness scores (coef = -0.0648; p = 0.001). These findings indicate that hormonal imbalances in adolescents with OD could affect personal growth. Further research is needed to establish causal relationships between the variables considered.
Vigil P et al., 2022·Front Endocrinol (Lausanne)·Free full text on PubMed Central
Obesity in women of reproductive age has a number of adverse metabolic effects, including Type II Diabetes (T2D), dyslipidemia, and cardiovascular disease. It is associated with increased menstrual irregularity, ovulatory dysfunction, development of insulin resistance and infertility. In women, estradiol is not only critical for reproductive function, but they also control food intake and energy expenditure. Food intake is known to change during the menstrual cycle in humans. This change in food intake is largely mediated by estradiol, which acts directly upon anorexigenic and orexigenic neurons, largely in the hypothalamus. Estradiol also acts indirectly with peripheral mediators such as glucagon like peptide-1 (GLP-1). Like estradiol, GLP-1 acts on receptors at the hypothalamus. This review describes the physiological and pathophysiological mechanisms governing the actions of estradiol during the menstrual cycle on food intake and energy expenditure and how estradiol acts with other weight-controlling molecules such as GLP-1. GLP-1 analogs have proven to be effective both to manage obesity and T2D in women. This review also highlights the relationship between steroid hormones and women's mental health. It explains how a decline or imbalance in estradiol levels affects insulin sensitivity in the brain. This can cause cerebral insulin resistance, which contributes to the development of conditions such as Parkinson's or Alzheimer's disease. The proper use of both estradiol and GLP-1 analogs can help to manage obesity and preserve an optimal mental health in women by reducing the mechanisms that trigger neurodegenerative disorders.
Duane M et al., 2022·Front Med (Lausanne)·Free full text on PubMed Central
Fertility awareness-based methods (FABMs) educate about reproductive health and enable tracking and interpretation of physical signs, such as cervical fluid secretions and basal body temperature, which reflect the hormonal changes women experience on a cyclical basis during the years of ovarian activity. Some methods measure relevant hormone levels directly. Most FABMs allow women to identify ovulation and track this "vital sign" of the menstrual or female reproductive cycle, through daily observations recorded on cycle charts (paper or electronic). Physicians can use the information from FABM charts to guide the diagnosis and management of medical conditions and to support or restore healthy function of the reproductive and endocrine systems, using a restorative reproductive medical (RRM) approach. FABMs can also be used by couples to achieve or avoid pregnancy and may be most effective when taught by a trained instructor. Information about individual FABMs is rarely provided in medical education. Outdated information is widespread both in training programs and in the public sphere. Obtaining accurate information about FABMs is further complicated by the numerous period tracking or fertility apps available, because very few of these apps have evidence to support their effectiveness for identifying the fertile window, for achieving or preventing pregnancy. This article provides an overview of different types of FABMs with a published evidence base, apps and resources for learning and using FABMs, the role FABMs can play in medical evaluation and management, and the effectiveness of FABMs for family planning, both to achieve or to avoid pregnancy.
Related research
Male Endocrine and Genetic Factors · Male Hormonal Axis
Some evidence suggests that infertile men, who are at increased risk for hypogonadism, metabolic derangements, and osteoporosis, have higher long-term morbidity and mortality than controls, but data are scarce and not conclusive.
We tested whether semen quality and reproductive function could represent a marker of general male health.
DESIGN, SETTING, A retrospective study of 5177 individuals from a prospectively collected database of 11516 males of infertile couples who had semen analysis in a tertiary university center.
OUTCOME MEASUREMENTS Of them, 5177 had all data for reproductive hormones, testis ultrasound, and biochemical determinations for glucose and lipid metabolism. Hypogonadism was defined as testosterone <10.5nmol/l and/or luteinizing hormone >9.4 IU/l. Individuals with a total sperm count of <10 million had genetic testing (karyotype, Y chromosome microdeletions, and CFTR gene mutations) and those with hypogonadism underwent dual-energy x-ray absorptiometry for bone mineral density. Descriptive statistics and odds ratio (OR) calculation were used.
Men with a low sperm count (<39 million/ejaculate) are at a high risk of hypogonadism (OR 12.2, 95% confidence interval [CI] 10.2-14.6) and have higher body mass index, waist circumference, systolic pressure, low-density lipoprotein cholesterol, triglycerides, and homeostatic model assessment (HOMA) index; lower high-density lipoprotein cholesterol; and a higher prevalence of metabolic syndrome (OR 1.246, 95 CI 1.005-1.545). All data are worse in men with hypogonadism, but a low sperm count per se is associated with a poor metabolic parameter. Men with hypogonadism have lower bone mineral density and 51% prevalence of osteoporosis/osteopenia. Longitudinal studies are necessary to support these data.
This is the largest study with comprehensive evaluation of semen quality and reproductive function, etiology and risk factor determination, and metabolic, cardiovascular, and osteoporosis risk assessment, performed in men referred for fertility evaluation. A low sperm count is associated with poorer metabolic, cardiovascular, and bone health. Hypogonadism is mainly involved in this association, but a low sperm count in itself is a marker of general health.
This large study evaluated semen quality, reproductive function, and metabolic risk in men referred for fertility evaluation, and showed that a man's semen count is a marker of his general health. Men with low sperm counts are more likely than those with normal sperm counts to have greater body fat, higher blood pressure, higher "bad" (low-density lipoprotein) cholesterol and triglycerides, and lower "good" (high-density lipoprotein) cholesterol. They also have a higher frequency of metabolic syndrome and insulin resistance, a condition that can lead to diabetes. Men with low sperm counts had a 12-fold increased risk of hypogonadism or low testosterone levels, and half of them had osteoporosis or low bone mass. Fertility evaluation gives men the unique opportunity for health assessment and disease prevention.
Metabolic syndrome (MetS) is highly prevalent, affecting more than 47 million US residents. This condition is also multifaceted, potentially leading to significant disturbance of numerous physiologic processes. This review article evaluates the literature regarding metabolic syndrome and male reproductive health. Links between obesity, dyslipidemia, hypertension, and insulin resistance are each examined with regard to their associated detrimental effects on male fertility. At the end of this manuscript, we propose a new MetS/male infertility paradigm. Additional studies specifically addressing the components of MetS and their impact on male reproduction will enhance our understanding of the underlying pathophysiology. These studies may also help clarify the role for therapeutic intervention.
Zańko A et al., 2022·International journal of environmental research and public health·Free full text on PubMed Central
Infertility is a problem that affects millions of couples around the world. It is known as a disease of couples, not individuals, which makes diagnosis difficult and treatment unclear. Male infertility can have many causes, from mechanical ones to abnormal spermatogenesis or spermiogenesis. Semen quality is determined by a number of factors, including those dependent on men themselves, with the number of infertile men growing every year. These include, e.g., diet, physical activity, sleep quality, stress, among many others. As these factors co-exist with insulin resistance, which is a disease closely related to lifestyle, it has been singled out in the study due to its role in affecting semen quality. In order to examine connections between lifestyle, insulin resistance, and semen quality, a review of literature published from 1989 to 2020 in the following databases PubMed/Medline, EMBASE (Elsevier), Scopus, Web of Science, and Google Scholar was performed. Hence, semen quality, environment, and insulin resistance are interrelated, thus it is difficult to indicate which aspect is the cause and which is the effect in a particular relationship and the nature of possible correlations. Since the influence of lifestyle on semen quality has been extensively studied, it is recommended that more thorough research be done on the relationship between insulin resistance and semen quality, comparing the semen quality of men with and without insulin resistance.
Previous reports of an association between low testosterone levels and diabetes risk were often confounded by covariation of sex hormone-binding globulin (SHBG) and testosterone measurements. Measurements of bioavailable and free testosterone, more reliable indexes of biologically active testosterone, were examined for their associations with markers of insulin resistance and body fat measures in 221 middle-aged nondiabetic men. Bioavailable and free testosterone were calculated from the concentrations of total testosterone, SHBG, and albumin, and they were not significantly correlated with SHBG (r = 0.07-0.1). In contrast, total testosterone correlated significantly with SHBG (r = 0.63). We evaluated the relationship between these measures of circulating testosterone and markers for insulin resistance (i.e., fasting insulin, C-peptide, and homeostasis model assessment for insulin resistance [HOMA-IR]) as well as total body fat (assessed by dual-energy X-ray absorptiometry [DEXA]) and abdominal fat distribution (assessed by single-slice computed tomography [CT]). Bioavailable, free, and total testosterone and SHBG all correlated significantly with fasting insulin (age-adjusted r = -0.15 [P = 0.03], -0.14 [P = 0.03], -0.32 [P < 0.0001], and -0.38 [P < 0.0001], respectively), fasting C-peptide (r = -0.18 [P = 0.009] to -0.41 [P < 0.0001]), HOMA-IR (r = -0.15 [P = 0.03] to - 0.39 [P < 0.0001]), and body fat measures (r = -0.17 [P = 0.008] to -0.44 [P < 0.0001]). Only SHBG and total testosterone were significantly associated with fasting glucose (r = -0.20 [P = 0.003] to -0.21 [P = 0.002]). In multivariate analysis, bioavailable or free testosterone was significantly and inversely associated with insulin, C-peptide, and HOMA-IR, but this was not independent of total body or abdominal fat. SHBG was a significant determinant of insulin, C-peptide, and HOMA-IR, independent of body fat. The associations between total testosterone and insulin resistance were confounded by SHBG. The inverse association between testosterone and insulin resistance, independent of SHBG, was mediated through body fat.
Male Fertility › Male Endocrine and Genetic Factors › Male Hormonal Axis
Ana M Salgado, Pilar Vigil, Patricio H Contreras
A Salgado, P Vigil, P Contreras
PMID 29998109 29998109 DOI 10.3389/fmed.2018.00190 10.3389/fmed.2018.00190 Contreras et al. 2018, Contreras 2018
Cite this article
Contreras, P. H., Serrano, F. G., Salgado, A. M., & Vigil, P. (2018). Insulin Sensitivity and Testicular Function in a Cohort of Adult Males Suspected of Being Insulin-Resistant. Frontiers in medicine, 5, 190. https://doi.org/10.3389/fmed.2018.00190
Contreras PH, Serrano FG, Salgado AM, Vigil P. Insulin Sensitivity and Testicular Function in a Cohort of Adult Males Suspected of Being Insulin-Resistant. Front Med (Lausanne). 2018;5:190. doi:10.3389/fmed.2018.00190
Contreras, P. H., et al. "Insulin Sensitivity and Testicular Function in a Cohort of Adult Males Suspected of Being Insulin-Resistant." Frontiers in medicine, vol. 5, 2018, pp. 190.
