Paternity through use of assisted reproduction technology in male adult and childhood cancer survivors : A nationwide register study

STUDY QUESTION: How does a history of cancer affect the likelihood of using assisted reproduction in order to achieve paternity? SUMMARY ANSWER: As compared to men with no history of cancer, use of assisted reproduction to achieve paternity was more frequent in fathers with a history of cancer, mainly those with testicular, prostate, and hematological and lymphatic malignancies. WHAT IS KNOWN ALREADY: Although it is well known that different types of cancer and their treatment may have a negative impact on fertility, there is a lack of data regarding the use of IVF and ICSI among male cancer survivors. STUDY DESIGN, SIZE, DURATION: In this population-based nation-wide study using the Swedish Medical Birth Register, we identified all men who fathered their first-born child in Sweden between 1994 and 2014. Using personal identification numbers, anonymized data from the Swedish National Quality of Assisted Reproduction Register, Swedish Cancer Register, Swedish Multi-generation Register, and Swedish Education Register were linked with the Swedish Medical Birth Register. PARTICIPANTS/MATERIALS, SETTING, METHODS: During the study period, a total of 1 181 488 men fathering their first-born child were identified. Of these, 26 901 fathers had a cancer diagnosis. Fathers diagnosed with cancer with <12 months from offspring conception, or with a cancer diagnosis after offspring conception, were excluded (n = 21 529). The remaining fathers who had a history of cancer (n = 5372) were divided into three groups based on age at cancer diagnosis (<15, ≥15 and <24, or ≥24 years). For subgroup analyses, they were also grouped according to the cancer location using ICD-7 codes. The fathers with no cancer diagnosis (n = 1 154 587), were included as controls. In total, 1 159 959 men were included. Associations between IVF/ICSI use and history of cancer were evaluated using logistic regression models, unadjusted and adjusted for paternal education, fathers age at childbirth, and year of conception, yielding crude and adjusted odds ratio (aOR), respectively, with a 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: As compared to controls, childhood cancer survivors were only more likely to achieve paternity through ICSI (aOR 3.52, 95% CI 2.52-4.93; P < 0.001) but not through IVF treatment (aOR 1.02, 95% CI 0.61-1.70; P = 0.955). Similarly, teenage and young adult cancer survivors were more likely to father through ICSI treatment (aOR 6.84, 95% CI 5.64-8.30; P < 0.001) but not using IVF (aOR 1.27, 95% CI 0.90-1.80; P = 0.17). However, adult cancer survivors were more likely to conceive through either ICSI (aOR 5.52, 95% CI 4.86-6.27; P < 0.001) or IVF treatment (aOR 1.32, 95% CI 1.09-1.60; P = 0.004). In subgroup analyses, childhood survivors of testicular cancer (aOR 5.15, 95% CI 1.20-22.0; P = 0.027), soft tissue and bone cancers (aOR 4.70, 2.13-10.4; P < 0.001), hematological and lymphatic cancers (aOR 4.49, 95% CI 2.72-7.40; P < 0.001), or central nervous system (CNS) and eye cancers (aOR 2.64, 95% CI 1.23-5.67; P = 0.012), were at an increased likelihood of fathering through ICSI. Teenage and young adult survivors of testicular cancer (aOR 15.4, 95% CI 11.5-20.7; P < 0.001), hematological and lymphatic cancers (aOR 9.84, 95% CI 6.93-14.0; P < 0.001), or soft tissue and bone cancers (aOR 6.83, 95% CI 3.53-13.2; P < 0.001) were more likely to father through ICSI treatment. Adult survivors of prostate cancer (aOR 15.7, 95% CI 6.70-36.9; P < 0.001), testicular cancer (aOR 9.54, 95% CI 7.81-11.7; P < 0.001), hematological and lymphatic cancers (aOR 11.3, 95% CI 8.63-14.9; P < 0.001), digestive, respiratory, and urogenital tract cancers (aOR 2.62, 95% CI 1.75-3.92; P < 0.001), CNS and eye cancers (aOR 2.74, 95% CI 1.48-5.08; P = 0.001), or skin cancer (aOR 1.68, 95% CI 1.08-2.62; P = 0.022) were more likely to father through ICSI treatment. Only teenage and young adult survivors of hematological and lymphatic cancers (aOR 1.98, 95% CI 1.10-3.56; P = 0.022) and adult survivors of testicular cancer (aOR 1.88, 95% CI 1.37-2.58; P < 0.001) were significantly more likely to achieve fatherhood using IVF treatment. LIMITATIONS, REASONS FOR CAUTION: Information on men failing to father children was not available, and thus our results cannot estimate the risk of infertility in men with a history of cancer. WIDER IMPLICATIONS OF THE FINDINGS: Use of ART, in particular ICSI, was significantly more frequent in fathers with malignancies of the male reproductive tract or hematological and lymphatic systems. Our findings highlight which groups of male cancer survivors would benefit from access to fertility care, thereby improving future fertility treatment policies. STUDY FUNDING/COMPETING INTEREST(S): The study received funding from the Swedish Cancer Society, Swedish Childhood Cancer Society, and the Swedish Government Fund for Clinical Research. There are no competing interest. TRIAL REGISTRATION NUMBER: N/A

Andrologisk undersökning bör ingå i infertilitetsutredningen

Impaired semen quality is present in approximately 50% of all infertile couples, indicating decreased fertility in the male. The etiology is unknown in 40-60% of the cases and standard semen parameters provide limited information about the cause and the chance for pregnancy in vivo or in vitro. Assessment of sperm DNA strand breaks may therefore be useful for optimal infertility treatment. Since the causes of infertility of the male part are largely unknown, few options for treatment of decreased semen quality are at hand. This applies to pharmacological and surgical methods as well as lifestyle related interventions. There are studies showing that infertile men have a significant risk of hypogonadism and shorter life expectancy due to higher risk of cardiovascular and metabolic diseases as well as certain cancers. Poor fertility can hence be considered as an early marker of general disease. Andrological examination, not only limited to semen analysis, but also including clinical, endocrinological and in some cases genetic evaluation should be part of the routine work-up of infertile couples

Urothelial carcinoma in remnant ureter in kidney transplanted patient after bilateral native nephrectomy - a rare case and literature review

The occurrence of primary ureteral carcinoma of the remnant ureter after nephrectomy for benign disease is very rare, and such cases in a kidney transplanted patient are even rarer. The case of a 62-year-old female patient is presented who had end stage autosomal dominant polycystic kidney disease and in 1991 underwent cadaveric kidney transplantation. Immunosuppression therapy was maintained with evorolimus and prednisolone. Normal serum creatinine levels were maintained and no signs of allograft rejection were detected. In 2010, the patient developed intermittent macroscopic haematuria and was admitted for further evaluation. Computer tomography, cystoscopy, laboratory tests and urine cytology were performed and no apparent reason for the haematuria was found. After more episodes of uncontrollable haematuria, in 2011 she underwent bilateral nephrectomy of her native kidneys. In 2015, after another episode of haematuria, a CT was performed on the patient. She was diagnosed with a solid enhancing mass in the right ureteral stump. Ureterectomy with bladder cuff excision was performed with lower midline laparotomy. The specimen was verified as high grade urothelial carcinoma, in stage T1 according to the 2004 WHO grading system. To the best of the authors’ knowledge, this is first case in the availabe literature of the occurrence of transitional cell carcinoma developing in the remnant ureter in a kidney transplanted patient after bilateral prophylactic nephrectomy for uncontrollable haematuria – 24 years after transplantation

Testosterone deficiency and metabolic disturbances in men who fathered a child by use of donated spermatozoa

Dose-response association between level of impairment of semen quality and risk of morbidity or premature death has been reported. Therefore, it can be presumed that men utilizing donated spermatozoa, i.e. patients with non-obstructive azoospermia, are at highest risk for adverse health outcomes. To evaluate the risks of prescription of medications for common metabolic disturbances and testosterone replacement therapy (TRT) among men who father children with donated spermatozoa-who presumably do it due to severe impairment of fertility. We used Swedish nationwide register data on all fathers who had a live-born child between 2007 and 2014 in order to compare men who fathered children with donated spermatozoa to the ones who became fathers by using own gametes. Cox regression analysis was used in order to estimate the post-conception incidence of prescription of medicines for hypertension (HT), diabetes (type 1 and 2), dyslipidaemia (DLE) or TRT. Starting the follow up at time of conception, models were adjusted for age, educational level, and previous cancer treatment. In total 410,119 childbirths were included in the analysis. Among them, for 390 fathers donated spermatozoa were utilized. Fathers to children conceived with donated spermatozoa had higher risk for having TRT prescribed (HR: 18.14; 95%CI: 11.71-28.10; p ≪ 0.001). Same was true for DLE (HR: 2.08; 95%CI: 1.27-3.39; p = 0.003) but not diabetes. Fathers to children conceived by use of donated spermatozoa are at significantly increased risk for testosterone treatment and dyslipidaemia, necessitating stringent follow up and inclusion in prevention programs

Testosterone replacement therapy in men who conceived with intracytoplasmic sperm injection: nationwide register study

Objectives Male hypogonadism is associated with higher risk of co-morbidity and premature mortality. It is, therefore, of utmost importance to identify young men who are at the highest risk of testosterone deficiency and who may benefit from preventive measures. In this context, infertile men constitute a high-risk group. The extent of testosterone replacement therapy (TRT) among infertile men, defined as men who have to undergo assisted reproduction for fatherhood, is currently unknown. Therefore, we evaluated the pattern of prescription of TRT in the years following child conception among men who have fathered children with the help of intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF). Design By sourcing data from national population registries, hazard ratio (HR) for subsequent TRT was assessed for IVF and ICSI-treated men and compared to those who conceived spontaneously with age Cox regression analysis adjusted for age, educational level and previous intake of medicines for metabolic diseases. Results ICSI and IVF fathers had increased incidence of newly prescribed TRT compared to fathers conceiving spontaneously (ICSI: HR = 3.81, 95% CI = 3.09–4.69, P < 0.001; IVF: HR = 1.54, 95% CI = 1.15–2.05, P = 0.003). After adjustment for prescription of medication for one or more components of the MetS prior to TRT, the risk estimates attenuated but remained robust both for ICSI-treated (HR = 3.17 (95% CI: 2.56–3.9) and IVF-treated men (HR = 1.06 (95% CI: 1.05–1.07). Conclusion Men who have to utilise powerful techniques, such as ICSI for fathering children, may be at risk for testosterone deficiency. Routine endocrine evaluation of men seeking fertility treatment is hence warranted

Impact of genetic risk score on the association between male childlessness and cardiovascular disease and mortality

Childless men are reported to have a higher risk of cardiovascular disease (CVD) and mortality. Information on inherited genetic risk for CVD has improved the predictive models. Presuming that childlessness is a proxy of infertility we aimed to investigate if childless men inherit more often genetic traits for CVD and if combining genetic and parenthood information improves predictive models for CVD morbidity and mortality. Data was sourced from a large prospective population-based cohort where genetic risk score (GRS) was calculated using two sets of either 27 (GRS 27) or 50 (GRS 50) single nucleotide polymorphisms (SNPs) previously found to be associated with CVD. Part of the participants (n = 2572 men) were randomly assigned to a sub-cohort with focus on CVD which served as an exploratory cohort. The obtained statistically significant results were tested in the remaining (confirmatory) part of the cohort (n = 9548 men). GRS distribution did not differ between childless men and fathers (p-values for interaction between 0.29 and 0.76). However, when using fathers with low GRS as reference high GRS was a strong predictor for CVD mortality, the HR (95% CI) increasing from 1.92 (1.10–3.36) for GRS 50 and 1.54 (0.87–2.75) for GRS 27 in fathers to 3.12 (1.39–7.04) for GRS50 and 3.73 (1.75–7.99) for GRS27 in childless men. The confirmatory analysis showed similar trend. Algorithms including paternal information and GRS were more predictive for CVD mortality at 5 and 10 years follow-ups when compared to algorithms including GRS only (AUC 0.88 (95% CI 0.84–0.92) and 0.86 (95% CI 0.84–0.90), and, AUC 0.81 (95% CI 0.75–0.87) and 0.78 (95% CI 0.73–0.82), respectively). Combining information on parental status and GRS for CVD may improve the predictive power of risk algorithms in middle-aged men. Childless men and those with severe infertility problem may be an important target group for prevention of CVD

Sex hormone-dependent and-independent regulation of serum BAFF and TNF in cohorts of transgender and cisgender men and women

Background: The risk of inflammatory diseases is sex-dependent, but it remains unknown whether this is due to the impact of sex hormones or sex chromosomes. Transgender individuals represent a unique cohort for studying the relative influence of endocrine and chromosomal factors. Here we compared serum levels of B-cell activating-factor (BAFF) and tumor necrosis factor (TNF) in transgender men (TM), transgender women (TW), cisgender women (CW) and cisgender men (CM). Methods: BAFF and TNF were measured in the serum of 26 CW, 30 CM, 27 TM and 16 TW individuals. To determine the responsiveness of immune cells, TNF was measured in bacterial lipopolysaccharide (LPS)-treated peripheral leukocytes. Results: BAFF was higher in CF (998 pg/mL) and TW (973 pg/mL) compared to CM (551 pg/mL) (P < 0.0001) and TM (726 pg/mL) (P < 0.0001). No difference in BAFF levels was shown between subjects grouped according to the number of X chromosomes. TNF was higher in CM (174 pg/mL) than TW (2.3 pg/mL) (P = 0.027) and TM (27.4 pg/mL) (P = 0.028). LPS-induced TNF was higher in CM (2524 pg/mL) and TM (2078 pg/mL) than in CW (1332 pg/mL) (both P < 0.0001) and TW (1602 pg/mL) (both P = 0.009). Discussion: Sex hormones and sex chromosomes have different impacts on cytokines involved in the sex-dependent inflammatory response. The concentration of BAFF and LPS-stimulated TNF secretion depended on sex hormone levels, whereas basal TNF was regulated by both sex hormone-dependent and-independent factors

Increased risk for prostate cancer related mortality among childless men in a population-based cohort followed for up to 40 years

Based on a nationwide register data we recently reported a link between male infertility and increased risk of early onset prostate cancer. However, mortality due to prostate cancer, which can be regarded as the ultimate proxy for its clinical significance, especially in the context of over-diagnosis and over-treatment, could not be explored in the previous study, since the follow-up period in most cases was too short. Data therefore must be retrieved from other cohorts, with longer follow-up. We sourced data from a population-based prospective cohort including 11,343 men aged over 45 years, enrolled in the 1970s. The results showed that childless men have higher risk for prostate cancer related mortality (HR: 1.49, 95% CI: 1.09–2.03, p = 0.01) compared to men with children, in particular when only married men, who most probably are involuntary childless, were considered (HR 1.54, 95% CI 1.13 − 2.10, p = 0.006). However, the prostate cancer incidence did not differ (HR = 1.04, 95% CI: 0.88–1.24). In conclusion, our results show that childless men are at higher risk for dying from prostate cancer, probably due to a more aggressive form of the disease

Risk of prostate cancer for men fathering through assisted reproduction: nationwide population based register study

Objective To compare the risk and severity of prostate cancer between men achieving fatherhood by assisted reproduction and men conceiving naturally.Design National register based cohort study.Setting Sweden from January 1994 to December 2014.Participants 1 181 490 children born alive in Sweden during 1994-2014 to the same number of fathers. Fathers were grouped according to fertility status by mode of conception: 20 618 by in vitro fertilisation (IVF), 14 882 by intra-cytoplasmic sperm injection (ICSI), and 1 145 990 by natural conception.Main outcome measures Prostate cancer diagnosis, age of onset, and androgen deprivation therapy (serving as proxy for advanced or metastatic malignancy).Results Among men achieving fatherhood by IVF, by ICSI, and by non-assisted means, 77 (0.37%), 63 (0.42%), and 3244 (0.28%), respectively, were diagnosed as having prostate cancer. Mean age at onset was 55.9, 55.1, and 57.1 years, respectively. Men who became fathers through assisted reproduction had a statistically significantly increased risk of prostate cancer compared with men who conceived naturally (hazard ratio 1.64, 95% confidence interval 1.25 to 2.15, for ICSI; 1.33, 1.06 to 1.66, for IVF). They also had an increased risk of early onset disease (that is, diagnosis before age 55 years) (hazard ratio 1.86, 1.25 to 2.77, for ICSI; 1.51, 1.09 to 2.08, for IVF). Fathers who conceived through ICSI and developed prostate cancer received androgen deprivation therapy to at least the same extent as the reference group (odds ratio 1.91; P=0.07).Conclusions Men who achieved fatherhood through assisted reproduction techniques, particularly through ICSI, are at increased risk for early onset prostate cancer and thus constitute a risk group in which testing and careful long term follow-up for prostate cancer may be beneficial