Fulghesu, A. M., Ciampelli, M., Fortini, A., Cucinelli, F., Guido, M., Caruso, A., Lanzone, A., & Mancuso, S. (1995). Effect of opioid blockade on insulin metabolism in polycystic ovarian disease. Human reproduction (Oxford, England), 10(9), 2253-2257. https://doi.org/10.1093/oxfordjournals.humrep.a136279
Fulghesu AM, Ciampelli M, Fortini A, Cucinelli F, Guido M, Caruso A, et al. Effect of opioid blockade on insulin metabolism in polycystic ovarian disease. Hum Reprod. 1995;10(9):2253-2257. doi:10.1093/oxfordjournals.humrep.a136279
Fulghesu, A. M., et al. "Effect of opioid blockade on insulin metabolism in polycystic ovarian disease." Human reproduction (Oxford, England), vol. 10, no. 9, 1995, pp. 2253-2257.
For EndNote, Zotero or Mendeley:
License
No open license is recorded for this paper. Reuse terms are set by the publisher.
A total of 17 women affected by polycystic ovarian disease (PCOD) were studied to evaluate the involvement of endogenous opioids in the pathophysiology of the hyperinsulinism in PCOD by administering naltrexone, an oral opioid antagonist. An oral glucose tolerance test (OGTT) was performed at baseline (on day 5 of the cycle) and repeated after 6 weeks of naltrexone administration. Plasma glucose, insulin and connecting peptide (c-peptide) concentrations were evaluated in all samples. Based on their insulinaemic response to OGTT, patients were classified as hyperinsulinaemic or normoinsulinaemic. Naltrexone treatment significantly (P < 0.007) reduced the insulin response to OGTT in the hyperinsulinaemic group without affecting the c-peptide incremental area; in the normoinsulinaemic group there was a slight, but not significant, increase in both c-peptide and insulin incremental areas. The two groups showed similar c-peptide incremental areas after naltrexone treatment. There was no significant difference in the c-peptide:insulin incremental areas molar ratio between the two groups; after treatment, a significant increase in this ratio was observed in both groups. When we considered the data as an expression of the fractional hepatic extraction of insulin, we found a lower value for hyperinsulinaemic in comparison with normoinsulinaemic patients (not significant), and a significant (P < 0.01) improvement of this parameter in the hyperinsulinaemic group after naltrexone administration. In conclusion, we suggest that the contribution to hyperinsulinaemia in PCOD patients may be at least in part due to both increased pancreatic secretion and reduced hepatic removal of insulin. Chronic pharmacological inhibition of opioid tone could improve the insulin plasma concentration by acting chiefly on the liver metabolism of insulin in hyperinsulinaemic patients.
Mazzilli R et al., 2026·Journal of endocrinological investigation
Male factor could contribute, alone or in combination with female factor, to the inability to conceive in a couple in more than half of cases. The effect of male factor infertility (MFI) on embryological assisted reproductive technology (ART) outcomes remains an ongoing discussion.
to evaluate the impact of MFI on embryo aneuploidy rates, to better understand the role and possible indication for Preimplantation genetic testing for aneuploidies (PGT-A), considering the role of sperm characteristics, paternal age, sperm DNA fragmentation and sperm aneuploidies.
this narrative review included all available articles, published up to January 2026.
Available evidence, often based on heterogeneous and old-fashioned methodologies, suggests that MFI may impair embryonic development, particularly in terms of fertilization rate and blastulation rate, more than embryo euploidy; however, a comprehensive evaluation of MFI should be integrated into clinical practice in the context of couple infertility, to also optimize the efficiency and outcomes of ART. Promising results emerged from sperm DNA fragmentation as a tool to predict embryo euploidy, but further investigations involving larger sample sizes and improved standardization are required.
Bulletti FM et al., 2025·Ther Adv Reprod Health·Free full text on PubMed Central
Infertility affects around 17.5% of reproductive-aged individuals worldwide, posing significant personal and public health challenges. Although Medically Assisted Reproduction and Assisted Reproductive Technology (ART; e.g., in vitro fertilization) have advanced outcomes, many couples fail to conceive due to unaddressed pelvic, uterine, or systemic factors. We aim to (1) define the current usage of Restorative Reproduction Medicine (RRM) in clinical practice, (2) compare RRM outcomes with conventional ART, and (3) propose an integrated model of RRM plus ART for optimal fertility care.
A systematic review following PRISMA guidelines was conducted (INPLASY registration no. INPLASY2024110069). Data sources and We searched PubMed, Scopus, and Web of Science (January 1995–October 2024), combining terms such as “restorative reproductive medicine,” “intrauterine adhesions,” “myomas,” “polyps,” “hydrosalpinx,” “endometritis,” “BMI,” “thyroid dysfunction,” “microbiome,” and “assisted reproductive technology.” Inclusion criteria: studies on uterine/systemic factors affecting infertility, focusing on surgical/pharmacological RRM interventions and ART limitations. Exclusion criteria: male-only infertility, case reports, narrative reviews, non-English publications. Quality assessment employed the Newcastle-Ottawa Scale and the Cochrane Risk of Bias Tool. We also briefly noted potential publication bias due to language and study-type restrictions. From >25,000 initial titles, 3 sequential screenings yielded 145 key articles addressing uterine (septum, myomas, polyps, adhesions) and systemic (body mass index (BMI) extremes, thyroid dysfunction, microbiome imbalance) factors. Surgical corrections (e.g., hysteroscopic removal of polyps/myomas, salpingectomy for hydrosalpinx) significantly improved natural conception and ART success (⩾20%–40% increase in clinical pregnancy). Chronic endometritis treatment, endometrial microbiome modulation, and BMI/thyroid optimization further improved pregnancy rates by 15%–20%. Comparisons of RRM versus ART alone indicated that RRM often lowers overall cost and may reduce miscarriage, while ART offers immediate embryo transfer. Combining RRM to correct pathologies prior to ART can boost implantation and live birth rates (⩾40%–70% improvement in some studies). Restorative Reproductive Medicine comprehensively addresses pelvic and systemic abnormalities, thereby enhancing fertility outcomes and complementing ART. A proposed integrated model—RRM diagnostics/interventions followed by ART if needed—maximizes success, reduces time/cost, and emphasizes holistic reproductive health. Further multicenter trials are warranted to standardize protocols and fully realize RRM’s potential in modern fertility care.
Mazzilli R et al., 2025·Andrology·Free full text on PubMed Central
To examine the association between semen parameters, assessed according to World Health Organization (WHO)-2021 criteria, and paternal body mass index (BMI) and age, with embryological and clinical outcomes in ICSI cycles involving preimplantation genetic testing for aneuploidy (PGT-A).
Retrospective study at a private in vitro fertilization (IVF) clinic.
3101 couples undergoing 4013 intracytoplasmic sperm injection (ICSI) + PGT-A cycles with own-oocytes (years 2013-2021).
We performed trophectoderm biopsy, and comprehensive chromosome testing to report uniform aneuploidies and vitrified-warmed euploid single-blastocyst-transfers. Regression analyses adjusted for relevant confounders were conducted to outline putative associations of semen analysis and characteristics and paternal BMI and age with all embryological/clinical outcomes.
Maternal age was the only significant confounding variable affecting euploidy blastocyst rate (EBR) (primary embryological outcome). When categorized, motility < 5th-percentile (-2.5%, 95%CI -4.9 to -0.2%, p = 0.03), concentration plus morphology < 5th-percentile (-2.7%,95%CI -4.8 to -0.6%, p = 0.01), concentration plus morphology plus motility < 5th-percentile (-4.0%,95%CI -5.5 to -2.6%, p < 0.01), obstructive-azoospermia [OA] (-5.5%,95%CI -9 to -2%, p = 0.02) and non-obstructive azoospermia (NOA) (-5.8%,95%CI -10.9 to -0.6%, p = 0.03) showed significantly lower results compared to all parameters > 5th-percentile. Furthermore, after adjusting for maternal age and the number of metaphase-II-oocytes inseminated, the only significant confounding variable affecting the chance of obtaining ≥ 1 live birth among completed cycles (primary clinical outcome) was basal and post sperm processing motility. When categorized, concentration plus morphology plus motility < 5th-percentile (multivariable-OR: 0.73, 95%CI 0.58-0.93, p = 0.01) and OA (multivariable-OR: 0.47, 95%CI 0.24-0.92, p = 0.03) showed significantly lower chances compared to all parameters > 5th-percentile. Advanced paternal age (defined as > 44 years) was associated only with lower day 5-blastocyst and Gardner's AA-grade (i.e., top quality) blastocyst rates.
This comprehensive analysis provides IVF professionals with useful figures to counsel infertile couples about their chances of success, taking into account the impact of semen characteristics and paternal BMI and age. These estimates are valuable for personalized decision-making about the most effective reproductive strategies to adopt, especially not underestimating male factor, by improving sperm concentration and motility whenever possible before assisted reproductive technologies.
Garolla A et al., 2020·Front Endocrinol (Lausanne)·Free full text on PubMed Central
This expert opinion summarizes current knowledge on risk factors for infertility and identifies a practical clinical and diagnostic approach for the male and female partners of an infertile couple aimed to improve the investigation and management of fertility problems. Infertility represents an important and growing health problem affecting up to 16% of couples worldwide. In most cases, male, female, or combined factor can be identified, and different causes or risk factors have been related to this condition. However, there are no standardized guidelines on the clinical-diagnostic approach of infertile couples and the recommendations concerning infertility are sometimes lacking, incomplete, or problematic to apply. The aim of this work is to provide an appropriate clinical and diagnostic pathway for infertile couples designed by a multidisciplinary-team of experts. The rationale is based on the history and physical examination and then oriented on the basis of initial investigations. This approach could be applied in order to reduce variation in practice and to improve the investigation and management of fertility problems. Prominent Italian experts of the main specialties committed in the ART procedures, including gynecologists, andrologists, embryologists, biologists, geneticists, oncologists, and microbiologists, called "InfertilItaly group", used available evidence to develop this expert position. Starting from the individuation of the principal risk factors that may influence the fertility of females and males and both genders, the work group identified most appropriate procedures using a gradual approach to both partners aimed to obtain a precise diagnosis and the most effective therapeutic option, reducing invasive and occasionally redundant procedures. This expert position provides current knowledge on risk factors and suggests a diagnostic workflow of infertile couples. By using this step-by-step approach, health care workers involved in ART, may individuate a practical clinical management of infertile couples shared by experts.
Related research
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
To evaluate the involvement of endogenous opiates in the pathophysiology of the hyperinsulinism in patients affected by polycystic ovary disease by administering naloxone and naltrexone. We also studied the hormonal status following long-term opioid antagonist administration. Twenty-one women affected by polycystic ovary disease participated in the study. An oral glucose tolerance test (GTT) was performed at baseline and repeated after short-term naloxone infusion and after 6 weeks of naltrexone administration. Plasma glucose and insulin levels were evaluated in all samples. Gonadotropins, sex hormone-binding globulin, and androgen levels were determined initially and after the naltrexone treatment. None of the patients showed any alteration of glucose tolerance. Based on the insulin response to the GTT, the patients were classified as normo- or hyperinsulinemic. Opioid antagonist administration significantly reduced the insulin response to the GTT in hyperinsulinemic patients, without affecting their glycemic levels. In normoinsulinemic patients, glucose plasma levels were increased whereas insulin levels were not modified by the treatments. Gonadotropin and androgen plasma concentrations were not modified after naltrexone administration. This work supports a role for the endogenous opiates in the regulation of exaggerated insulin secretion in patients with polycystic ovary disease. The reduction of insulin secretion failed to demonstrate any hormonal modification in such hyperandrogenized patients.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
We previously reported that circulating beta-endorphin levels are increased in obese hirsute women and that plasma immunoreactive insulin (IRI) levels are increased in proportion to the degree of hyperandrogenism in women with the polycystic ovary (PCO) syndrome. We, therefore, tested the hypothesis that endogenous opiates are at least partially responsible for the hyperinsulinemia and insulin resistance in this syndrome. In the first study, acute naloxone administration significantly reduced the plasma IRI response and IRI/glucose ratio in three euglycemic obese women with PCO and acanthosis nigricans (AN) and marked insulin resistance, but did not alter the glucose response. Naloxone had no effect on these parameters in the normal weight control subjects. In the second study, nalmefene, a new, orally active opiate antagonist, reduced IRI and the IRI/glucose ratio in four women with PCO-AN and marked hyperinsulinemia in a randomized, double blind, crossover protocol. We conclude that endogenous opiates are at least partially responsible for the hyperinsulinemia and insulin resistance in PCO-AN.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
Hadziomerovic D et al., 2006·Fertility and Sterility
Evaluation of the effects of naltrexone on hyperinsulinemia and hyperandrogenemia in hyperandrogenemic, hyperinsulinemic women. Controlled clinical study. Department of Gynecologic Endocrinology and Reproductive Medicine, Center of Obstetrics and Gynecology, Medical University of Innsbruck, Austria. PATIENT(S): Thirty-nine hyperandrogenemic, hyperinsulinemic women were studied. INTERVENTION(S): Women were treated with naltrexone (50 mg/d) for >or=3 weeks. MAIN OUTCOME MEASURE(S): Body mass index (BMI), gonadotropin (LH, FSH) and androgen (T, free T, DHEAS) levels, and plasma levels of glucose, insulin, and C-peptide, during a standard 75-g oral glucose tolerance test (OGTT), were determined before and during chronic opiate receptor blockade. RESULT(S): The BMI did not change during therapy. When OGTT was repeated after treatment with naltrexone, glucose levels were not different from those before treatment. Insulin response, however, had dramatically declined. We also observed a significant decrease in the levels of serum androgens. CONCLUSION(S): Hyperinsulinemia associated with hyperandrogenemia can be improved or completely abolished by chronic opiate receptor blockade. This observation suggests that endogenous opiates play a critical role in the process leading to hyperinsulinemia in hyperandrogenemia.
Hyperinsulinemia secondary to a poorly characterized disorder of insulin action is a feature of polycystic ovarian disease (PCOD). On the other hand, being generally admitted that opioids may play a role in glycoregulation and that opioid tone is altered in PCOD, an involvement of the opioids in determining the hyperinsulinemia of PCOD patients could be suggested. The aim of this study was to evaluate the effect of a chronic opioid blockade on insulin metabolism and peripheral insulin sensitivity in PCOD hyperinsulinemic patients. Twenty-three women with PCOD were studied. An oral glucose tolerance test (OGTT) and a clamp study were performed at baseline (during the follicular phase) and after 6 weeks of naltrexone administration (50 mg/d orally). Based on the insulinemic response to the OGTT, 16 women were classified as hyperinsulinemic and seven as normoinsulinemic. Naltrexone treatment significantly reduced fasting (P < .05) and area under the curve (AUC) (P < .02) plasma insulin levels only in the hyperinsulinemic group. Moreover, hyperinsulinemic patients showed similar C-peptide incremental areas after naltrexone treatment, whereas in the same patients the fractional hepatic insulin extraction calculated from the incremental areas of insulin and C-peptide was found to be increased after chronic opioid blockade by naltrexone. For peripheral insulin sensitivity, the hyperinsulinemic group showed significantly lower (P < .01) total-body glucose utilization (M) compared with the normoinsulinemic group. No change in the M value was found after treatment in both groups. These data suggest that the insulin sensitivity and hyperinsulinemia after an OGTT are two distinct deranged features of the insulin disorder of PCOD patients.
Anna Maria Fulghesu, Maurizio Guido, Antonio Lanzone, Mario Ciampelli
A Fulghesu, M Guido, A Lanzone, M Ciampelli
PMID 8530646 8530646 DOI 10.1093/oxfordjournals.humrep.a136279 10.1093/oxfordjournals.humrep.a136279 Fulghesu et al. 1995, Fulghesu 1995
Cite this article
Fulghesu, A. M., Ciampelli, M., Fortini, A., Cucinelli, F., Guido, M., Caruso, A., Lanzone, A., & Mancuso, S. (1995). Effect of opioid blockade on insulin metabolism in polycystic ovarian disease. Human reproduction (Oxford, England), 10(9), 2253-2257. https://doi.org/10.1093/oxfordjournals.humrep.a136279
Fulghesu AM, Ciampelli M, Fortini A, Cucinelli F, Guido M, Caruso A, et al. Effect of opioid blockade on insulin metabolism in polycystic ovarian disease. Hum Reprod. 1995;10(9):2253-2257. doi:10.1093/oxfordjournals.humrep.a136279
Fulghesu, A. M., et al. "Effect of opioid blockade on insulin metabolism in polycystic ovarian disease." Human reproduction (Oxford, England), vol. 10, no. 9, 1995, pp. 2253-2257.
