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Elsevier Editorial System(tm) for Fertility and Sterility Manuscript Draft

Manuscript Number: Title: Endocrine, Cellular and Molecular Effects of Diabetes on Male Fertility Article Type: Modern Trends Keywords: Diabetes; Male fertility; Sperm; HPT axis; DNA Damage. Corresponding Author: Dr Ishola Michael Agbaje, MB Bch BAO PhD Corresponding Author's Institution: Queens University First Author: Ishola Agbaje, PhD Order of Authors: Ishola Agbaje, PhD; Brew Atkinson, MD; Sheena Lewis, PhD; Neil McClure, MD Abstract: Diabetes Mellitus (DM) is the commonest endocrine disorder in man. Given the available evidence, there can be little doubt that it has the potential to impair male reproductive function at a number of levels via a variety of mechanisms. Beyond its well-recognised effects on male sexual function, recent evidence suggests that it is associated with damage to sperm at a molecular level. Such damage has been shown to be potentially associated with infertility, early pregnancy loss and childhood disease. The prevalence of DM is increasing rapidly worldwide. As a consequence many more men will be affected prior to and during their reproductive years. Thus, at a population level, the impact of DM on male fertility may become increasingly apparent with time. This paper reviews the available literature examining the effects of DM on various aspects of male reproductive function both in humans and in animal models of DM.

Suggested Reviewers: Allan Pacey BSc PhD Senior Lecturer in Andrology, Academic Unit of Reproductive and Developmental Medicine, University of Sheffield [email protected] Respected clinical andrologist with a research background Juan Alvarez PhD Reproductive Medicine, Institut Marques [email protected] Acknowledged expert in molecular aspects of sperm and male infertility Iwan Lewis-Jones PhD Clinical Andrologist, Hewitt Centre for Reproductive Medicine , Liverpool Women’s Hospital [email protected] Respected clinical andrologist with extensive research background.

Opposed Reviewers:

* Cover Letter

Edward E. Wallach, M.D., Johns Hopkins Division of Reproductive Endocrinology and Infertility, Foxleigh Building, Suite 301, 2330 West Joppa Road, Lutherville, Maryland 21093

10th June 2009

Dear Professor Wallach,

Further to my recent correspondence with Mr Steinmehl, on behalf of my co authors and myself, I would like to submit our manuscript entitled “Endocrine, Cellular and Molecular Effects of Diabetes on Male Fertility” for consideration for the ‘Modern Trends’ section of Fertility and Sterility. This manuscript reviews the effects of Diabetes on male reproductive function, a much-neglected aspect of diabetic care. Our group has a research interest in this area and has published several original articles in a number of reproductive journals. The paper has not been submitted nor is under consideration in any other journal.

The reviewers we would like to suggest are:

Dr. Allan Pacey BSc PhD Senior Lecturer in Andrology Academic Unit of Reproductive and Developmental Medicine Level 4 The Jessop Wing Tree Root Walk Sheffield S10 2SF Telephone: +44 (0) 114 226 8290 Fax: +44 (0) 114 226 1074 Email: [email protected]

Dr Juan G Alvarez Institut Marques Pº Manuel Girona 33, MASIA 08034 Barcelona Spain Tel: +34.932.858.216 Fax: +34.932.059.155 Email: [email protected]

Dr Iwan Lewis-Jones Hewitt Centre for Reproductive Medicine Liverpool Women’s Hospital Crown Street Liverpool L8 7SS Tel: 0151 702 4215 Fax: 0151 702 4342 Email: [email protected]

None of the authors have any conflict of interests and the signed statements will be faxed to the editorial office in due course. Should you have any enquiries, I would welcome the opportunity of answering your questions. We keenly await your view and that of the reviewers. Yours sincerely,

Dr Ishola Agbaje PhD MRCOG Subspeciality Trainee in Reproductive Medicine/Research Fellow Department of Obstetrics and Gynaecology Queens University of Belfast Tel: +44 2890 632506 Email: [email protected]

* Manuscript

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Running Title

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Diabetes and Male Reproductive Function.

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Endocrine, Cellular and Molecular Effects of

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Diabetes on Male Fertility

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Ishola Agbaje PhD1,3, Brew Atkinson MD2, Sheena Lewis PhD1 and Neil McClure MD1,3

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Reproductive Medicine Research Group, Queen's University, Belfast, UK.

Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast, UK. Regional Fertility Centre, Royal Maternity Hospital, Belfast, UK.

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Correspondence:

Dr Ishola Agbaje

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Reproductive Medicine Research Group

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Queen's University, Belfast

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Institute of Clinical Science

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Royal Victoria Hospital

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Grosvenor Road, Belfast, BT12 6BJ.

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E-mail: [email protected]

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Financial Support: Northern Ireland Research and Development Office (Grant number

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EAT 2539).

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Capsule

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Diabetes impairs male reproductive function at several levels through a variety of

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mechanisms. The rising prevalence of this disease poses another threat to male fertility.

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(26 words)

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Abstract

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Diabetes Mellitus (DM) is the commonest endocrine disorder in man. Given the available

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evidence, there can be little doubt that it has the potential to impair male reproductive

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function at a number of levels via a variety of mechanisms. Beyond its well-recognised

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effects on male sexual function, recent evidence suggests that it is associated with

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damage to sperm at a molecular level. Such damage has been shown to be potentially

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associated with infertility, early pregnancy loss and childhood disease.

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The prevalence of DM is increasing rapidly worldwide. As a consequence many more

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men will be affected prior to and during their reproductive years. Thus, at a population

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level, the impact of DM on male fertility may become increasingly apparent with time. This

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paper reviews the available literature examining the effects of DM on various aspects of

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male reproductive function both in humans and in animal models of DM.

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(148 words)

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Key words:

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Diabetes, Male fertility, Sperm, HPT axis, DNA Damage

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Introduction

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Epidemiology of Diabetes

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The prevalence of Diabetes Mellitus (DM) is increasing rapidly. By the year 2025 it is

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estimated that over 300 million people will be affected worldwide (1, 2). As a result, over

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the next 25 years, DM will emerge as one of the world’s leading causes of morbidity and

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mortality (2). Obesity, population growth and aging, as well as a reduction in physical

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activity, have been cited as likely explanations for this increase (1). Given its familial

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tendency, it has also been proposed, that factors such as the improved management of

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infertility associated with polycystic ovarian syndrome (a disorder associated with a high

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incidence of type-2 DM in later life) and the near normal obstetric outcomes now achieved

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in diabetic pregnancies, may also contribute, by significantly expanding the ‘diabetic gene

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pool’ in a way that has previously been limited by nature (3).

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The increasing prevalence of DM is not restricted to older age groups; children and

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adolescents are also increasingly affected. In European children, type-1 DM is rising by

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3% per annum (4). As a result, the next ten years will see a 50% increase in prevalence,

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making it the commonest endocrine disorder in children (5). Coupled with this, type-2 DM

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is now recognised to occur much more frequently in younger individuals. In the United

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States alone, it is estimated to account for up to 76% of diabetes in the teenage years (6).

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Unlike other autoimmune diseases, type-1 DM does not show a predilection for females.

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On the contrary, an excess of males are affected in a ratio of 3:2 (7, 8). In contrast, type-2

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DM affects both sexes equally (8). Whilst it is acknowledged that genetic factors are

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important in the development of DM, the nature of this relationship is complex. The

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offspring of women rather than men with type-2 DM are more likely to develop the

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disease (8). In contrast, the offspring of men with type-1 DM are almost three times more

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likely to develop diabetes than that of females with type-1 DM (9, 10).

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The epidemiological changes described above will result in many more men being

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affected by DM prior to and during their reproductive years. Although its effects on female

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reproduction have been extensively investigated (see reviews by (11, 12)), there are

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comparatively few studies specifically reporting its impact on male reproductive function

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and fertility beyond its effect on male potency. This review examines the available

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literature both in humans and in animal models of DM.

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Male infertility

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Infertility is a major health problem in both the developed and developing world, with

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approximately 1 in 6 couples requiring specialist help for the investigation or treatment of

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infertility (13, 14). Around 60-80 million couples worldwide require medical help to

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conceive (WHO 1997 Progress in Reproductive Health). This is strikingly illustrated by the

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fact that in Europe alone, up to 6% of children are born following artificial reproductive

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technologies (ART) including in vitro fertilisation (IVF) (15, 16).

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It is widely believed that human male fertility has been declining for some time. A

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reduction in sperm counts has been reported over the last 50 years (17) and a variety of

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lifestyle and environmental factors have been implicated. Disorders of spermatogenesis

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and sperm function are recognised to be causative or contributory in up to 50% of sub-

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fertile couples (18, 19). The purported decrease is further supported by the increasing use

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of technologies such as intracytoplasmic sperm injection (ICSI) (15), a treatment primarily

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used for the treatment of severe male factor infertility.

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Could the rising incidence of DM in men of reproductive age represent an additional

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burden to an already declining male fertility? If so, the male preponderance of type-1 DM

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and the enhanced risk to their offspring of developing the disease, may serve to further

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compound this problem. Despite this, to date, the majority of research examining male

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reproductive function in DM has focused mainly on its effects on sexual function, with

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comparatively few studies evaluating male fertility either directly or indirectly.

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Diabetes and Male Fertility

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Human Studies

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There have been no large-scale prospective clinical studies evaluating either the

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fecundity or reproductive outcomes of men with DM. Indirect evidence from a study of

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sub-fertile men found 1% were diabetic (20). This figure was much greater than that

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predicted (0.3%) given the prevalence of male infertility and diabetes in these

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populations, thus implying a negative association between DM and male fertility. Indeed,

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the importance of excluding significant medical pathology, such as DM, during the

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evaluation of male infertility is acknowledged (21). More recent studies (22) have reported

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a similar prevalence of DM in male partners of infertile couples. Despite this, in the clinical

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setting, DM is still not seen as a particularly relevant issue in the assessment of male

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fertility.

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To our knowledge, the only study examining reproductive outcomes in pregnancies

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fathered by diabetic men (23), reported significantly higher rates of miscarriage (17% vs

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11%, p4

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months) (29). In contrast, a reduction in pituitary gonadotrophins has been observed in

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numerous studies of rats with STZ-induced diabetes (25, 26, 42-47).

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Although no differences were observed in basal gonadotrophin levels of diabetic infertile

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human subjects (39), Baccetti et al. reported a decreased pituitary response to

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exogenous GnRH stimulation. This suggests that DM may lead to a reduction in the pool

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of pituitary gonadotrophin available for release. Further evidence for this comes from a

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study of poorly controlled type-1 diabetic men (48), in which a reduced (50%) LH

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response to pulses of exogenous GnRH was observed, resulting in a ‘central

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hypogonadotrophism’. This group concluded that insulin deficiency itself in type-1

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diabetes was the main factor causing these alterations in hypothalamic GnRH release

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and pituitary responsiveness.

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Impaired release of hypothalamic GnRH may contribute to the reduced availability of

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pituitary gonadotrophins. Immunohistochemical studies have shown morphological

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changes in the hypothalamus and pituitary of diabetic animals suggesting the impaired

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release of both LHRH and LH (49). Furthermore, changes in the metabolism of

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hypothalamic LHRH and neurotransmitters have also been reported in diabetic rats (46,

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50). Although serum LH levels were depressed in the STZ rat, Frenkel et al. found similar

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amounts of LHRH and LH in the hypothalamus and pituitary of diabetic and control

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animals (25). Furthermore, serum LH levels were restored with exogenous LHRH. They

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postulated that the reduction LH was secondary to impaired release of LHRH, which

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although sufficient to support LH synthesis, was inadequate to facilitate its secretion from

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the anterior pituitary.

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Testicular Endocrine Function

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Variable effects of diabetes on testosterone and free testosterone levels in diabetic men

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have been reported, with normal (36, 37, 39, 48, 51-53), increased (38, 54, 55), or

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decreased (40, 41, 56) serum levels being observed. In contrast, a reduction in

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testosterone, (25, 26, 43, 45-47) appears to be a consistent feature in spontaneous and

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experimentally induced animal models of diabetes.

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Normal testosterone levels have been reported in the presence of a normal LH (37, 39).

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However, Handelsman et al. (36) reported a normal testosterone despite significantly

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raised gonadotrophin levels, implying a failure of Leydig cell synthesis or an impairment of

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the testosterone-mediated feedback control of LH secretion. Further evidence for Leydig

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cell dysfunction comes from the finding of a blunted testosterone response to exogenous

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human chorionic gonadotrophin stimulation (hCG) (used as an LH analogue) and the

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accumulation of lipid in Leydig cells of diabetic animals (28) representing a block in

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testosterone synthesis (29). The ensuing reduction in intra-testicular testosterone may

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well be the primary event triggering the subsequent testicular and spermatogenic

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abnormalities in these animals (29).

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In contrast, a study of poorly controlled type-1 diabetic men (48), reported normal

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testosterone levels in the presence of a reduced serum LH. In these subjects, androgen

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levels were maintained because of an increase in bioactive gonadotrophin molecules,

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which maintained testosterone levels despite a reduction in the absolute gonadotrophin

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levels.

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A number of studies have reported reduced testosterone levels in the presence of normal

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pituitary gonadotrophins (40, 41, 56). Although Leydig cell dysfunction is thought to be

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responsible for this (41), its response to exogenous GnRH (40) and hCG (48) has been

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unimpaired in some reports, suggesting impairment at the level of the hypothalamus or

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pituitary.

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Sex Hormone Binding Globulin (SHBG) and Free Testosterone

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Only a small proportion of serum testosterone (