Fertility and diabetes. D. Carvalho (Portugal)

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1 Fertility and diabetes D. Carvalho (Portugal)

2 Diabetes and Fertility Davide Carvalho Department of Endocrinology, Diabetes and Metabolism Centro Hospitalar S. João/ Faculty of Medicine University of Porto Instituto de Investigação e Inovação em Saúde

3 Disclosures Nothing to disclose regarding this presentation

4 Summary Introduction Fertility and autoimmunity Diabetes, fertility and endocrine disruptors: Is there a link?

Introduction Infertility Definition: inability to conceive after 1 year of unprotected intercourse Global Prevalence: 9% Developed countries: 3.5-16.7% Portugal: 8.

5 Introduction Infertility Definition: inability to conceive after 1 year of unprotected intercourse Global Prevalence: 9% Developed countries: % Portugal: 8.9% (Afrofite study: 151 of 1700; 29 69y; women) Developing countries: % Last Century: Reproductive diseases Reproductive function Populations are exposed to several potentially dangerous substances: some are called Endocrine Disruptors (ED). ED residues are present in the serum, seminal plasma and follicular fluid. Reproductive function reveals susceptibility to the effects of ED, leading to functional and morphologic abnormalities. Marques- Pinto A, Carvalho D. Human infertility: are endocrine disruptors to blame? Endocr Connect. 2013; 2 :R15-29; Carvalho J et al Afrodite study.

6 Introduction Several factors impair the chances of pregnancy Age, Endometriosis, Diabetes Mellitus, Ovarian Dysfunction, PCOS, Previous infection of the genitourinary tract Marques- Pinto A, Carvalho D. Human infertility: are endocrine disruptors to blame? Endocr Connect. 2013; 2 :R15-29; Carvalho J et al Afrodite study.

7 Introduction Diabetes and fertility Altered Spermatogenesis decrease in sperm motility and morphology. in all semen parameters (semen volume, sperm count, motility and morphology) levels of seminal fructose and glucose. in sperm motility. degenerative and apoptotic changes in testes. altered glucose metabolism in Sertoli/ blood testes barrier. Reduced testosterone synthesis and secretion, Ejaculatory dysfunction Reduced libido Barták V, et al. Juvenile diabetes and human sperm quality. Int J Fertil. 1975; 20: 30-32; Padron RS, et al. Semen analyses in adolescent diabetic patients. Acta Diabetol Lat 1984; 21: ; Ali ST, et al. Serum and urinary levels of pituitary-gonadal hormones in insulin dependent and non-insulin-dependent diabetic males with and without neuropathy. Arch Androl 1993; 30: ; Melendez-Ramirez LY, et al. Complications altered glucose meof type 1 diabetes. Endocrinol Metab Clin North Am 2010; 39: ; Jangir RN and Jain GC. Diabetes Mellitus Induced Impairment of Male Reproductive Functions: A Review. Current Diabetes Reviews, 2014, 10:

8 Introduction Diabetes and fertility Joslin - reported that girls with type 1 diabetes mellitus failed to develop menarche. Within 2 months to 1 year of insulin administration, however, menarche was observed in some of the girls. Before insulin treatment, most women with diabetes mellitus were either outright infertile or spontaneously aborted. Women with T1DM have considerably fewer children, and are more often childless than women without diabetes mellitus. T1DM affects female fertility similarly to other autoimmune diseases. Sen, A. et al. Endocrine autoimmune diseases and female infertility. Nat Rev Endocrinol. 2014;10:

9 Norwegian Mother and Child Cohort Study Substantially decreased fecundability for women with type 1 and type 2 diabetes 58,004 women: identified 221 cases of type 1 diabetes and 88 cases of type 2 diabetes Type (95% CI ) Type (95% CI ) 0 0,5 1 1,5 2 Whitworth K. W., et al. Fecundability among women with type 1 and type 2 diabetes in the Norwegian Mother and Child Cohort Study. Diabetologia 2011; 54:

10 Summary Introduction Fertility and autoimmunity Diabetes, fertility and endocrine disruptors: Is there a link?

11 Type 1 diabetes, automimmunity and female fertility Clinical association of autoimmunity with female infertility - controversial Implantation - female immune system >> tolerance to the embryo Hyperactive immune system incomplete tolerance >> reducing fertility and increasing the risk of miscarriage Autoimmunity >> affect female fertility by prematurely diminishing ovarian reserve, adversely affecting fertilization and implantation, and by increasing the risk of miscarriage and of various pregnancy complications Autoimmune endocrine diseases affect reproduction even at prodromal clinical stages, often months to years before diagnosis of the disease Sen, A. et al. Endocrine autoimmune diseases and female infertility. Nat Rev Endocrinol. 2014;10:

Auto-immune endocrine disease and fertility APS autoimmune polyglandular syndromes; DOR,diminished ovarian reserve;opoi, occult primary insufficiency; PCOS

12 Auto-immune endocrine disease and fertility APS autoimmune polyglandular syndromes; DOR,diminished ovarian reserve;opoi, occult primary insufficiency; PCOS Polycystic ovary syndrome;pof premature ovarian failure Sen, A. et al. Endocrine autoimmune diseases and female infertility. Nat Rev Endocrinol. 2014;10:

Delayed menarche in T1DM TIDM before and after menarche vs NHANES No association of delayed menarche with episodes of diabetic ketoacidosis or hypoglycemia, neither with BMI

13 Delayed menarche in T1DM TIDM before and after menarche vs NHANES No association of delayed menarche with episodes of diabetic ketoacidosis or hypoglycemia, neither with BMI or A1c Schweiger BM, Snell-Bergeon JK, Roman R, et al. Menarche delay and menstrual irregularities persist in adolescents with type 1 diabetes. Reprod Biol Endocrinol 2011;9:61.

14 Menstrual irregularities in T1DM Ovulatory cycles (%) Ovulatory rate (N/100days) A1c (%) Ovulatory rate (N/100days) Codner E, et al. Ovulation rate in adolescents with type 1 diabetes mellitus. Fertil Steril. 2011; 95:

15 Time to menopause in T1DM Type 1 diabetic women Non diabetic Dorman JS, Steenkiste AR, Foley TP, et al. Menopause in type 1 diabetic women: is it premature? Diabetes 2001;50:

16 Premature ovarian senescence (premature menopause or primary ovarian insufficiency) Prevalence ~10% of all women. Definition - amenorrhoea and FSH permanently 40.0 miu/ml before the age of 40 years. Anti-Müllerian hormone levels do not define premature ovarian failure. Occult Primary Ovarian Insufficiency (Premature Ovarian Ageing) represents ~90% of all premature ovarian senescence, characterized FSH (<40.0 miu/ml) under the age of 40 years and/or abnormally low age-specific levels of anti-müllerian hormone. Sen, A. et al. Endocrine autoimmune diseases and female infertility. Nat Rev Endocrinol. 2014;10:

17 A quarter of type 1 diabetic patients had low adrenal function without anti CYP21A atb Male Female Simunkova, K. Adrenocortical function in young adults with diabetes mellitus type 1. J Steroid Biochem Mol Biol 2010, 122:35-41

18 Adrenal Ovarian function in normoandrogenic, hypoandrogenic and hyperandrogenic Sen, A. et al. Endocrine autoimmune diseases and female infertility. Nat Rev Endocrinol. 2014;10:

19 Intracellular insulin cascade and Steroidogenesis

20 Androgen Supplementation In hypoandrogenic conditions of low ovarian reserve established a treatment paradigm, expanding interventions from the gonadotropinsensitive stage (last 2 weeks) into earlier follicle maturation stages. Insufficient knowledge about the interplay between autoimmunity and reproduction suggests that reproductive immunology is an urgent target area for multi-speciality research by reproductive biologists, rheumatologists, immunologists and endocrinologists. Sen, A. et al. Endocrine autoimmune diseases and female infertility. Nat Rev Endocrinol. 2014;10:

21 PCOS in T1DM US evidence of PCO is seen in 40% to 50% of adult type 1 diabetic women but only in 13% of agematched nondiabetic controls. The number of women using intensive insulin treatment is higher in women with evidence of PCOS. Under physiologic conditions, the insulin produced by the pancreas undergoes first-pass metabolism through the liver. This eliminates 50% to 70% of insulin secreted by the pancreas. Type 1 diabetic patients do not experience this 1stpass metabolism and thus have higher systemic insulin levels for similar glucose control. Sen, A. et al. Endocrine autoimmune diseases and female infertility. Nat Rev Endocrinol. 2014;10:

22 What constitutes proper diabetic control during fertility treatment and in pregnancy? Remained under dispute. Upper A1c levels of % define good glycaemic control for pregnant women with diabetes mellitus. Women with T1DM that is brittle, levels of HbA1c up to 7.0% are acceptable. Riskin-Mashiah, S. and Auslander, R. Quality of medical care in diabetic women undergoing fertility treatment: we should do better! Diabetes Care 2001; 34, Vargas, R.et al. Type 1 diabetes mellitus and pregnancy. Rev. Obstet. Gynecol. 2010; 3,

23 Summary Introduction Fertility and autoimmunity Diabetes, fertility and endocrine disruptors: Is there a link?

Exposure to Endocrine Disruptors Routes of exposure: ingestion and

Periods Immediate (morphological) Deferred (functional /metabolic /

24 Exposure to Endocrine Disruptors Routes of exposure: ingestion and occupational exposure Lipophilia Stability Acumulation Fetuses, infants and children have greater exposure. Intrauterine exposure may have lasting effects: Critical Periods Sensible Periods Immediate (morphological) Deferred (functional /metabolic / neoplastic) Marques- Pinto A, Carvalho D. Human infertility: are endocrine disruptors to blame? Endocr Connect. 2013; 2: R15-29.

25 Diabetes, fertility and endocrine disruptors: Is there a link? Endocrine Dysruptors ED combined combined with gene

Clinical aspects that could be related to ED Hypospadias

000 births Paulozzi 1997 Breast cancer Sperm count (x10 6

26 Clinical aspects that could be related to ED Hypospadias Testicular cancer Rate per births Paulozzi 1997 Breast cancer Sperm count (x10 6 /ml) USA Europe África Swan SH et al. Have sperm density declined? A reanalysis of global trend. Env Health Persp 1997;105: Ano de nascimento

Endocrine Disruptors Motley Crew: synthetic industrial substances, drugs and natural substances. Ligands of nuclear or membrane receptors modifying gene expression.

27 Endocrine Disruptors Motley Crew: synthetic industrial substances, drugs and natural substances. Ligands of nuclear or membrane receptors modifying gene expression. Completely different response Ability to alter hormone bioavailability: most have estrogenic or anti-androgenic activity. Dose-response: Standard toxicology assumes that as the dose of a chemical increases, so does its effect, and vice versa to the same hormone, possibly going through the same receptor system, in one tissue than you d have in another tissue. Marques- Pinto A, Carvalho D. Human infertility: are endocrine disruptors to blame? Endocr Connect. 2013; 2: R15-29.

28 Correlation between synthetic chemical production in the USA and prevalence of T2DM Neel BA, Sargis RM. The paradox of progress: environmental disruption of metabolism and the diabetes epidemic. Diabetes 2011;60:

29 In the Subcutaenous Adipose Tissue 73 premenopausal; 48 postmenopausal submitted to RYbypass p= p = p= Σ HCH (ng/g) p,p-dde(ng/g) XEs (ng/g) Pre-menopause Pos-menopause Teixeira D, Freitas P et al. Inflammatory and Cardiometabolic Risk on Obesity: Role of Environmental Xenoestrogens J Clin Endocrinol Metab 2015;100: epub ahead of print

30 XE levels were associated with metabolic dysfunction p= p< p< p< ns FPG (mg/dl) A1c (%) HOMA IR HOMA 2B 10y CV Risk Pre menopause Pos menopause Teixeira D, Freitas P et al. Inflammatory and Cardiometabolic Risk on Obesity: Role of Environmental Xenoestrogens J Clin Endocrinol Metab 2015;100: epub ahead of print

31 Teixeira D, Freitas P et al.. Inflammatory and Cardiometabolic Risk on Obesity: Role of Environmental Xenoestrogens J Clin Endocrinol Metab 2015;100: epub ahead of print

32 Effects of nuclear and extranuclear oestrogen receptor (ER) activation on glucose homoeostasis and ß-cell pancreatic islet function Chevalier N, Fénichel P. Endocrine disruptors: New players in the pathophysiology of type 2 diabetes? Diabetes & Metabolism 2015; 41:

33 Early life exposure to ED and Late Life Diseases Chevalier N, Fénichel P. Endocrine disruptors: New players in the pathophysiology of type 2 diabetes? Diabetes & Metabolism 2015; 41:

34 Type 1 diabetes and Fertility Conclusions - Female Before insulin treatment, most women with diabetes mellitus were either outright infertile or spontaneously aborted. Women with T1DM have considerably fewer children, and are more often childless than women without diabetes mellitus. T1DM affects female fertility similarly to other autoimmune diseases. Spontaneous ovulation improves with better glycaemic control, although even women with poorly controlled diabetes mellitus often still ovulate. This is a principal reason why, even in well-functioning health-care systems, women with T1DM often conceive without proper preconception care.

35 Type 1 diabetes and Fertility Conclusions - Female Preconception care is essential to reduce miscarriage and congenital anomaly risks, both closely associated with glycaemic control during the early weeks of pregnancy. Women with T1DM are usually more severely affected than those with T2DM. Even with maximal medical attention, women with T1DM demonstrate inferior pregnancy outcomes compared with healthy women. Preconception medical care of women with diabetes mellitus undergoing fertility treatment seems to be as poor as in those who spontaneously conceive, which suggests an urgent need for improved preconception counselling.

36 Type 2 diabetes, ED and Fertility Conclusions There is a need to extend the knowledge of the mechanisms of action of ED and XEs, which may alter metabolic function, which will open novel directions for the prevention, and treatment of metabolic disease The question of whether XEs could serve as biomarkers representing a novel tool to predict cardiometabolic risk remains to be fully answered, but if these findings are reproducible in different populations,

37 Ackowledgement

38 Let s meet in Porto!

Infertility: failure to conceive within one year of unprotected regular sexual intercourse. Primary secondary

Subfertility Infertility: failure to conceive within one year of unprotected regular sexual intercourse. Primary secondary Infertility affects about 15 % of couples. age of the female. Other factors that