to be associated with reduced testosterone levels secondary to insulin resistance [6]. Although sex hormone binding globulin (SHBG) level is low with insulin resistance, the free testosterone level has been shown to be low in one‐third of men with diabetes [7]. Clinically, this could present as hypogonadism with symptoms and biochemical evidence of testosterone deficiency.
Management options
The metabolic derangements in diabetes do not only have teratogenic effects during the period of organogenesis but may also program the offspring’s future risk of cardiovascular and metabolic disease [8]. The risks of miscarriage, congenital malformations and perinatal mortality are three times higher in women with poor control compared against women with optimal glycemic control [9]. Whatever the management options considered; all these risks must be taken into consideration.
Female with diabetes
For those known to have diabetes, preconception care and counseling (PCC) aim to optimize the woman’s physical, social and emotional wellbeing preconceptually, to ensure healthy intra‐uterine environment for the developing fetus [10]. This has been shown to significantly reduce the risk of major and minor congenital anomalies in women with established diabetes mellitus [11], hence is the most important management step for a patient with diabetes planning to conceive through ART. There is great consistency in international guidelines on preconception care for the patients with diabetes especially on recommendations such as multidisciplinary approach involving social health professionals and counselors, optimal preconception HbA1c of between 6–7 %, medication review with respect to feto‐maternal safety profile, commencing high dose (5mg daily) folic acid, screening and management of diabetic complications and advising appropriate contraception until optimal metabolic control is achieved [12]. In Case History 1 with a high HbA1c of 12%, the woman requires referral to the multidisciplinary team for optimization of her glycemic control and preconception counseling as per international guideline recommendations in order to reduce the risk of adverse feto‐maternal outcomes.
Ovarian hyperstimulation syndrome (OHSS) should always be ruled out in any symptomatic woman who has undergone controlled ovarian stimulation. In Case History 1, on day 5 after oocyte retrieval, the woman’s symptoms could be related to infection and she will therefore require ruling out of pelvic infection (appropriate diagnostic work up in order to initiate targeted treatment). Uncontrolled diabetes and infection are a dangerous combination and can predispose to diabetic ketoacidosis. A high index of suspicion and early involvement of the specialized multidisciplinary team are therefore warranted.
Females with bariatric surgery
Weight reduction and maintaining an optimum BMI, usually with the help of a dietician, helps diabetes control and ovarian response in those who are overweight or obese. Where the patient is morbidly obese and other approaches to weight reduction have failed, bariatric surgery is an option recognized to improve glycemic control in selected cases of type 2 diabetes mellitus [13,14]. In a survey of women planning bariatric surgery, future pregnancy was an important consideration for 30% [15]. A modern‐day fertility unit may therefore encounter diabetic women with a history of bariatric surgery and requesting ART treatment. Contemporaneous recommendation is to wait for at least 12 months after bariatric surgery before conception [16–18] to allow for the desired goals of surgery to be achieved. A multidisciplinary approach involving the primary surgical team is again warranted in this situation. Controlled ovarian hyperstimulation can be challenging in diabetic patients with polycystic ovary syndrome (PCOS) and would need special considerations including innovative stimulation regimens for maximum gains while avoiding complications at the same time [19].
Male with diabetes
In Case History 2, the symptoms and biochemical findings are consistent with hypogonadism, which is secondary to the patient’s uncontrolled type 2 diabetes and a high BMI. The first step in the management will involve weight reduction, as adipose tissue produces cytokines and adipokines which lead to metabolic dysfunction and insulin resistance, which further contribute to a low total serum testosterone. A reduction in BMI will help with the control of diabetes, improve erectile dysfunction (ED) and testosterone levels [20]. Referral to a diabetologist is required to help achieve tight glycemic control which may improve the semen profile.
For diagnosis and treatment of hypogonadism, the recommendation from a panel of European and US testosterone experts are (a) to provide testosterone therapy if the total testosterone levels are < 8nmol/L and (b) in those with total testosterone of 8–12 nmol/L and hypogonadal symptoms consider a trial of testosterone therapy [21]. There is evidence that testosterone replacement therapy improves insulin sensitivity and glycemic control [22]. However, testosterone therapy adversely affects spermatogenesis and thus may not be an appropriate intervention in a man trying to achieve conception, especially if the sperm results are already poor pretreatment or if the couple is already planning for ART through ICSI.
ED, which is common in men with diabetes, could be because of hypogonadism or the vascular and neuropathic effects of diabetes. Men with ED may therefore respond to phosphodiesterase inhibitors.
Statins are hydroxymethylglutaryl‐CoA reductase inhibitors, which can potentially reduce testosterone levels by decreasing availability of cholesterol for testosterone biosynthesis. Studies have shown conflicting results of statin treatment on testosterone levels. However, there is evidence to suggest that in type 2 diabetes, statins lower testosterone levels [23]. Serum lipid profile should be repeated in this case and if normal, after appropriate counseling, statins can be withheld temporarily while the couple undergoing is ICSI treatment.
Prevention
For patients with diabetes undergoing ART, tight glycemic control is associated with normal ovarian response, fertilization and cleavage rates and pre‐embryonic development. Preconception counseling for good glycemic control is the basis for a good pregnancy outcome. Optimal BMI maintenance is required for better glycemic control. In patients with diabetes, prophylactic antibiotics during oocyte retrieval should be considered to reduce the risk of infection. Thrombo‐embolic risk assessment should be conducted, and appropriate thrombo‐prophylaxis instituted where indicated.
In men with diabetes, androgen status should be checked if they have symptoms of hypogonadism or if they are taking statins. Good glycemic control and optimal BMI are required for maintaining normal serum testosterone levels and semen parameters. Those with ED should be considered for a trial with phosphodiesterase inhibitors and advised to arrange a backup storage of frozen sperm in case they fail to produce sperm on the day of oocyte retrieval, or alternatively oocytes could be frozen if there were no sperm.
Key points
Challenge: Patients with diabetes requiring ART.
Background:
More and more couples with diabetes are seeking ART due to the global rise in the prevalence of diabetes mellitus and impaired glucose intolerance.
Diabetes affects male and female gametes.
In men, type 2 diabetes is associated with hypogonadism and erectile dysfunction.
Uncontrolled diabetes in pregnancy is not only teratogenic during the period of organogenesis with increased risk of miscarriage but also programs the offspring’s future risk of cardiovascular and metabolic diseases.
Management options:
Multidisciplinary
