The hypothalamus–pituitary–ovary axis and type 1 diabetes mellitus: a mini review

Human Reproduction Vol.21, No.2 pp. 327–337, 2006 doi:10.1093/humrep/dei353 Advance Access publication October 20, 2005. The hypothalamus–pituitary–ovary axis and type 1 diabetes mellitus: a mini review R.F.Arrais1,3 and S.A.Dib2 1 Children and Adolescent Endocrinology Unit, Department of Pediatrics, Federal University of Rio Grande do Norte, 59010-180, Natal, RN and 2Division of Endocrinology, Federal University of São Paulo, 04039-002, São Paulo, SP, Brazil 3 To whom correspondence should be addressed: Departamento de Pediatria, Universidade Federal do Rio Grande do Norte – UFRN, Av. General Cordeiro de Farias, s/n, Petrópolis, 59010-180, Natal, RN, Brasil. E-mail: Key words: Diabetes/fertility/hyperandrogenism/menarche/menstrual dysfunction Introduction Systematic studies of the metabolic effects of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) on the hypothalamus–pituitary–ovary (HPO) axis have revealed a relationship between these diseases and menstrual disturbances, such as delayed menarche, alterations in the menstrual rhythm (including primary and secondary amenorrhoea) and potential consequences on fertility and fecundity. Currently, through consideration of their aetiology and the natural history of their development, it is accepted that T1DM and T2DM are two distinct diseases. It is convenient, therefore, to consider their effects on the HPO axis separately. Typically, T1DM patients present some dysfunction in this axis at the age of menarche (Adcock et al., 1994; Yeshaya et al., 1995), and this is most pronounced when diabetes occurs before or at the pre-pubertal stage. The symptoms associated with T1DM include accentuated delay of menarche and menstrual cycle irregularities, i.e. amenorrhoea, oligomenorrhoea and polymenorrhoea (Yeshaya et al., 1995; Strotmeyer et al., 2003), as well as precocious menopause and lower fertility (Yeshaya et al., 1995, Dorman et al., 2001; Durando et al., 2003). With respect to T2DM, correlations between the disease and fertility, the age of onset of menopause and alterations in the length of the menstrual cycle have been reported (Durando et al., 2003). Variations in insulin sensitivity, which are normally observed during the menstrual cycle, are typically exacerbated in patients with menstrual irregularities. These abnormalities may be considered as a possible indicator for predicting the risk of glucose intolerance or of the development of T2DM (Pulido and Salazar, 1999; Cooper et al., 2000; Solomon et al., 2001) within the general population and especially in high-risk groups such as the Pima Indian women of Arizona (Roumain et al., 1998). The present review focuses primarily on the alterations observed in the HPO axis of T1DM patients. General principles of the function of the HPO axis The hypothalamus plays a central role in the hormonal regulation of the female reproductive system. The sequence of events corresponding to the menstrual cycle is induced by the action of hormones released by the hypothalamus–pituitary system on the ovarian follicle (Carr, 1998). The main regulatory factor of reproductive function is GnRH, a decapeptide secreted by the ventral medial nucleus of the hypothalamus. Production and further release of GnRH to the portal pituitary system are induced and controlled through stimuli received from other regions of the brain via mediators of different origins. © The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: 327 A high prevalence of menstrual cycle and fertility disturbances has long been associated with diabetes mellitus. However, rationalization of the intrinsic mechanisms of these alterations is controversial and even contradictory. This review considers (i) the relationship between diabetes mellitus, especially type 1 diabetes mellitus (T1DM), and the hypothalamus–pituitary–ovary (HPO) axis, (ii) the state of our knowledge concerning neuroendocrine control and its relationship with dopaminergic and opioid tonus, and (iii) the influence of the hypothalamus–pituitary–adrenal axis on ovarian function. Functional disturbances that occur as a consequence of diabetes are also discussed, but some T1DM-related diseases of autoimmune origin, such as oophoritis, are not further analysed. Although there are clear indications of a relationship between menstrual and fertility alterations and glycaemic control, in many instances the improvement of the latter is not sufficient to reverse such alterations. It appears that the oligoamenorrhoea and amenorrhoea associated with T1DM is mainly of hypothalamic origin (i.e. failure of the GnRH pulse generator) and may be reversible. The importance of the evaluation of the HPO axis in T1DM women with menstrual irregularities, even in the presence of adequate metabolic control, is emphasized. R.F.Arrais and S.A.Dib Amino acids Glutamate and γ-aminobutyric acid (GABA) are considered, with other neurotransmitters, to be important synaptic regulators, exerting their functions through secretion by hypothalamic nuclei on post-synaptic specific receptors, leading to stimulation (glutamate) or inhibition (GABA) of GnRH neurons (Reichlin, 1998). Biogenic amines Hormones Prolactin has several effects on gonadotrophin secretion, mainly inhibiting LH and FSH secretion at the pituitary level. Estradiol has a diphasic effect on the mature pituitary and on hypothalamic GnRH neurons, firstly inhibiting and secondly stimulating its release. LH and FSH exert negative short loop feedback control of GnRH secretion and negative ultrashort loop feedback control of its own secretion (autocrine feedback). Progesterone also has inhibitory direct effects on GnRH neurons. Inhibin, an inhibitory regulator produced by the gonads, and activin, a specific FSH releaser, with follistatin (which inhibits the binding of activin to its receptor) are major regulators of FSH action in women (Reichlin, 1998; Rosenfield, 2002). Opioid system Endogenous opium-like peptides, or endorphins, comprise several substances (met-enkephalin, leu-enkephalin, melanocortin, β-endorphin) derived from pro-opiomelanocortin (POMC; a precursor); they inhibit the release of GnRH. Antagonistic action of naloxone usually increases LH and FSH secretion. There is strong evidence that gonadotrophin secretion is regulated by interaction between dopamine and endogenous opioids, although it is not clear if this regulation is carried out directly or is mediated via the dopaminergic system (Djursing, 1987; Reichlin, 1998). Peptides This class of organic substances comprises most of the protein compounds with hormonal activity at the hypothalamic 328 GnRH, LH/FSH and estrogen physiology GnRH regulates the synthesis, storage and mobilization of the gonadotrophins as well as their acute release (Carr, 1998). The mechanism of action of GnRH involves the binding of the hor (...truncated)