Despite Joslin’s early observations of abnormal ovarian function in women with type 1 diabetes mellitus, insulin was not thought to play a significant role in ovarian function until the late 1970s, when patients with extreme forms of insulin resistance were described. Manifestations of ovarian hypofunction (primary amenorrhea, late menarche, anovulation, and premature ovarian failure) in untreated type 1 diabetes mellitus can be understood if it is accepted that insulin is necessary for the ovary to reach its full steroidogenic and ovulatory potential.
Thus, patients with insulin deficiency commonly exhibit hypothalamic-pituitary and ovulatory defects, but not hyperandrogenism. On the other end of the clinical spectrum, women with syndromes of severe insulin resistance and consequent hyperinsulinemia exhibit anovulation associated with hyperandrogenism, as discussed above. If insulin is capable of stimulating ovarian androgen production in insulin resistant patients, one has to postulate that ovarian sensitivity to insulin in these patients is preserved, even in the presence of severe insulin resistance in the classical target organs, such as liver, muscle, and fat. To explain this paradox, we will briefly review cellular mechanisms of insulin action in the ovary and the relationships between insulin, insulin-like growth factors (IGFs), and their receptors. The term “insulin-related ovarian regulatory system” has been proposed to describe a complex system of ovarian regulation by insulin and IGFs. The components of this system include insulin, insulin receptors, insulin-like growth factor I (IGF-I), insulin-like growth factor II (IGF-II), type 1 IGF receptors, type 2 IGF receptors, IGF binding proteins (IGFBPs) 1-6, and IGFBP proteases. These ovarian insulin receptors are structurally and functionally similar to insulin receptors found in other organs .
Regulation of insulin receptor expression, however, may be somewhat different in the ovaries compared to other target tissues. While in classical target tissues insulin receptors are down-regulated by hyperinsulinemia, there is evidence that circulating factors other than insulin may regulate insulin receptor expression in the ovaries of premenopausal women. These factors may include sex steroids, gonadotropins, IGFs, and IGFBPs. The phenomenon of differential regulation of ovarian insulin receptors, with their preservation on cell membrane in spite of hyperinsulinemia, may provide one explanation for the ovarian responsiveness to insulin in premenopausal women with insulin resistance in peripheral target organs. The ovarian insulin receptors have heterotetrameric α2β2 structure, possess tyrosine kinase activity, and may stimulate the generation of inositolglycans. After insulin binds to the α-subunits of the insulin receptor, the β-subunits are activated via phosphorylation of the tyrosine residues and acquire tyrosine kinase activity, e.g., the ability to promote phosphorylation of other intracellular proteins. The intracellular proteins phosphorylated under the influence of the insulin receptor tyrosine kinase are the insulin receptor substrates (IRS) The insulin receptor activation and IRS phosphorylation result in the activation of phosphatidylinositol-3 kinase (PI-3-kinase). This activation is necessary for transmembrane glucose transport.
kinase (MAPK), responsible for DNA synthesis and gene expression, is also activated by insulin; MAPK
activation does not require activation of PI-3-kinase. Tyrosine kinase activation is the earliest postbinding event and is necessary for many of the effects of insulin. Although it is believed to be the main signaling mechanism of the insulin receptor, an alternative-signaling pathway involving the generation of inositolglycan second messengers has been described (see Fig. 33.2). This alternative pathway has been found to mediate several of the effects of insulin, including, possibly, ovarian steroid production. Thus, activation of MAP-kinase and inositolglycan signaling cascades follows pathways that are distinct from those involved in glucose transport. This phenomenon of postreceptor divergence of insulin signaling pathways helps explain how some of the effects of insulin may be normally preserved, or even over-expressed, in the presence of hyperinsulinemia observed in insulin resistant states. In fact, it has been demonstrated that some of the ovarian effects of insulin are PI-3-kinase independent.
Finally, the ovaries may remain sensitive to the actions of insulin in the presence of insulin resistance because, as mentioned above, insulin, when present in high concentration, can activate type 1 IGF receptors. This pathway of insulin action may be operative in patients with syndromes of extreme insulin resistance whose insulin receptors are rendered inactive by a mutation or by anti-insulin receptor antibodies. There is evidence that type 1 IGF receptors may be up-regulated in the presence of hyperinsulinemia both in animal models and in women with PCOS.
Recent studies suggested yet another pathway which explains preserved insulin sensitivity in the ovary by invoking insulin-induced activation of PPAR-γ gene. This activation was shown to have direct and indirect effects in the ovary (Table 33.2). Activation of PPAR-γ by PPAR-γ agonists, thiazolidinediones (TZD) (rosiglitazone or pioglitazone), has been shown to produce direct effects in the ovary, which can be both insulin-independent and insulin sensitizing. Another study demonstrated an interaction between PPAR-γ and insulin signaling pathways with steroidogenic acute regulatory (StAR) protein, thus, suggesting that PPAR-γ may represent a novel human ovarian regulatory system. In summary, the paradox of preserved ovarian sensitivity to insulin in insulin resistant states can be explained by differential regulation of insulin receptors in the ovaries of premenopausal women; by activation of signaling pathways distinct from those involved in glucose transport (inositolglycan and MAP-kinase pathways, rather than tyrosine kinase and PI-3 kinase pathways); by the activation of type 1 IGF receptors which may be up-regulated in the presence of hyperinsulinemia; and by activation of PPAR-γ gene leading to improvement in insulin sensitivity either by direct or indirect effects in the ovary (Table 33.3). In conclusion, in PCOS patients, ovarian sensitivity to insulin appears to be preserved and the insulin signaling pathways do not exhibit hypersensitivity.
Fig. 33.2 Insulin receptor, its signaling pathways for glucose transport, and hypothetical mechanisms of stimulation or inhibition of steroidogenesis. The main pathways for the propagation of the insulin signal include the following events: after insulin binds to the insulin receptor α-subunits, the β-subunit tyrosine kinase is activated; IRS-1 and -2 are phosphorylated; PI-3 kinase is activated; GLUT glucose transporters are translocated to the cell membrane, and glucose uptake is stimulated. An alternative-signaling system may involve generation of inositolglycans at the cell membrane after insulin binding to its receptor. This inositolglycan signaling system may mediate insulin modulation of steroidogenic enzymes. (Adapted, with permission, from L. Poretsky et al.15 ©The Endocrine Society)
Table 33.2 Effects of TZDs related to ovarian function (adapted with permission from Seto-Young et al.53)
Can be observed in vitro, may be present in vivo
Observed in vivo; are due to systemic
insulin-sensitizing action and reduction of
↑ Progesterone production
↓ Testosterone production
↓ Estradiol production
↑ IGFBP-1 production in the absence of
↓ Testosterone production
↓ Estradiol production
↑ IGFBP-1 production
↑ SHBG ↓free T
B. Insulin sensitizing (enhanced insulin effect)
↓ IGFBP-1 production
↑ Estradiol production (in vivo, in a setting
of high-dose insulin infusion)
Insulin Effects Related to Ovarian Function
Potential mechanisms underlying the gonadotropic activity of insulin include direct effects on steroidogenic enzymes, synergism with FSH and LH, enhancement of pituitary responsiveness to GnRH, and effects on SHBG and on the IGF/IGFBP systems (see Table 33.4). Investigations focused on these mechanisms have provided insights not only into normal ovarian physiology, but also into the pathogenesis of ovarian dysfunction in a wide spectrum of clinical entities, such as obesity, diabetes mellitus, PCOS, and syndromes of extreme insulin resistance.
Table 33.4 Insulin effects related to ovarian function
Directly stimulates steroidogenesis Ovary
Acts synergistically with LH and FSH to stimulate
Stimulates 17 α-hydroxylase Ovary
Stimulates or inhibits aromatase Ovary, adipose tissue
Up-regulates LH receptors Ovary
Promotes ovarian growth and cyst formation
synergistically with LH/hCG Ovary
Down-regulates insulin receptors Ovary
Up-regulates type I IGF receptors or hybrid insulin/type I IGF
Inhibits IGFBP-I production Ovary, liver
Potentiates the effect of GnRH on LH and FSH Pituitary
Inhibits SHBG production Liver
Up-regulates PPAR-γ Ovary
Activates StAR protein Ovary
Adapted, with permission, from L. Poretsky et al.15 ©The Endocrine Society
Effects on steroidogenesis. In vitro, insulin acts on the granulosa and thecal cells to increase production of androgens, estrogens, and progesterone. This action is likely mediated by the interaction of insulin with its receptors. Several in vitro studies, however, have demonstrated that supraphysiologic concentrations of insulin are needed to achieve this steroidogenic effect on the ovary, suggesting that, under some circumstances, insulin action may be mediated via the type 1 IGF receptor. Studies that attempted to determine whether insulin stimulates or inhibits aromatase or 17-α-hydroxylase have resulted in contradictory conclusions. For example, Nestler et al. reported that 17-α-hydroxylase activity appears to be stimulated by insulin, but Sahin et al. in a later study found no relation between insulin levels and 17-hydroxyprogesterone (17-OHP) after treatment with GnRH agonist.
One study showed that, after gonadotropin infusion, hyperinsulinemic women with PCOS had an increased estradiol/ androstenedione ratio compared with women with PCOS and normal insulin levels, thus suggesting insulin’s stimulatory effect on aromatase. However, in other studies increased circulating levels of androstenedione were found during insulin infusions, suggesting that insulin inhibits aromatase. Ovarian androgen production in response to insulin has also been extensively studied in vivo both directly, in the course of insulin infusions, and indirectly, after a reduction of insulin levels by insulin sensitizers or other agents, such as diazoxide. While insulin infusion studies did not produce consistent evidence of increased androgen production, reduction of insulin levels has consistently resulted in decreased androgen levels. Synergism with LH and FSH on the stimulation of steroidogenesis. At the ovarian level, insulin has been demonstrated to potentiate the steroidogenic response to gonadotropins. This effect is possibly caused by an increase in the number of LH receptors that occurs under the influence of hyperinsulinemia.
Enhancement of pituitary responsiveness to GnRH. Another area of uncertainty is whether insulin enhances the sensitivity of gonadotropes to GnRH in the pituitary. Several investigators have demonstrated increased responsiveness of gonadotropes to GnRH in the presence of insulin in cultured pituitary cells. Nestler and Jakubowicz showed decreased circulating levels of LH in patients treated with insulin sensitizers. But in another study, gonadotropin responsiveness to GnRH did not change after insulin infusion. Similarly, in rats with experimentally produced hyperinsulinemia, response of gonadotropins to GnRH does not appear to be altered. The effect on SHBG. Insulin has been shown to suppress hepatic production of sex hormone-binding globulin (SHBG). Lower levels of SHBG result in increased serum levels of unbound steroid hormones, such as free testosterone. In PCOS and other hyperinsulinemic insulin resistant states, insulin may increase circulating levels of free testosterone by inhibiting SHBG production. When insulin sensitizers are used, SHBG levels rise, thereby decreasing free steroid hormone levels. The effect on IGFBP-1. Insulin has been found to regulate insulin-like growth factor-binding protein-1 (IGFBP-1) levels. In both liver and ovarian granulosa cells, insulin inhibits IGFBP-1 production.
Lower circulating and intraovarian IGFBP-1 concentrations result in higher circulating and intraovarian levels of free IGFs that may contribute to increased ovarian and adrenal steroid secretion.Type 1 IGF receptor. Insulin increases ovarian IGF-I binding in rats, suggesting an increase in the expression of ovarian type 1 IGF receptors or hybrid insulin/type 1 IGF receptors. In these studies, ovarian type 1 IGF receptors are up-regulated even though insulin receptors are either down-regulated or preserved. Studies in women with PCOS appear to confirm this phenomenon.PPAR-γ . Insulin increases expression of PPAR-γ in vitro in human ovarian cells. Activation of PPAR-γ enhances steroidogenesis via activation of StAR protein (Fig. 33.3). StAR protein. In addition to being activated through PPAR-γ, StAR protein can be also activated by insulin directly via insulin signaling pathway (Fig. 33.3).
Ovarian growth and cyst formation. It has been shown that insulin enhances theca-interstitial cell proliferation in both human and rat ovaries. In a report of a patient with the type B syndrome of insulin resistance, infusion of insulin resulted in a significant increase of ovarian volume with sonogram demonstrating that the ovaries doubled in size. Experimental hyperinsulinemia in synergism with hCG produces significant increase in ovarian size and development of polycystic ovaries in rats (Fig. 33.4). In summary, in a number of in vitro animal and human ovarian cell systems and in vivo experiments in animals and in women a variety of insulin effects related to ovarian function have been demonstrated. These effects can account for many features of PCOS in hyperinsulinemic insulin resistant women. Insulin effects related to ovarian function are summarized in Table 33.4.
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