| Endocrine and metabolic changes in women with polycystic ovaries and with polycystic ovary syndrome | ||
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Aside from establishing fertility, inducing ovulatory cycles and improving hirsutism, one important aim in the treatment of PCOS women is to reduce the incidence of the long-term consequences of metabolic sequelae.
The symptoms of hyperandrogenism frequently bring the patient to medical attention. Drug treatment is directed at suppressing ovarian or adrenal sources of androgens or blocking androgen action in the skin.
Oral contraceptives (OC) have been shown to be moderatly effective in reducing circulating androgen levels by up to 50% and in alleviating hirsutism (Givens et al. 1974). They suppress gonadotrophin secretion (Givens et al. 1974), reduce ovarian androgen secretion (Wild et al. 1982), increase SHBG synthesis thereby decreasing androgen action and inhibit DHT binding to androgen receptors (Eil & Edelson 1984). The administration of OCs alone is often effective in the treatment of acne. The combination of OCs with antiandrogen seems to be necessary in moderately or severe cystic acne and hirsutism (Rittmaster 1995).
Cyproterone acetate (CPA) is a potent progestin, a moderatly potent antiandrogen and a weak glucocorticoid. It acts as a competitive inhibitor of androgens by binding to their receptors, reduces 5α-reductase in the skin, and lowers ovarian androgen secretion by inhibiting gonadotrophin release (Neumann et al. 1970). It can be orally administered at a daily dose of 25-50 mg from days 1 to 10 of the cycle and is available as an OC (2 mg CPA in combination with 35 µg of ethinylestradiol) (Rittmaster 1995). An improvement of hirsutism is usually seen after 3 to 6 months of treatment (Kuttenn et al. 1980). Suppression of ovarian function by the use of GnRHa has also been succesful in the improvement of hirsutism (Adashi 1990, Rittmaster & Thompson 1990, Tiitinen et al. 1994).
Spironolactone binds competitively to the androgen receptor with 67% of the affinity of DHT (Eil & Edelson 1984). It is also a weak progestin and weak inhibitor of T biosynthesis. Spironolactone is usually administered orally at 25 to 100 mg twice daily (Crosby & Rittmaster 1991) and can be used together with OCs. Spironolactone alone is as effective in the treatment of hirsutism as OC with CPA (Spritzer et al. 2000).
Flutamide is a nonsteroidal antiandrogen widely used in the treatment of prostate cancer. It has no progestational, estrogenic, glucocorticoid or antigonadotropic activities. It is administered orally in the treatment of hirsutism at a dose of 125-250 mg twice daily with or without OC. Its efficacy is comparable with spironolactone and CPA (Erenus et al. 1994, Grigoriou et al. 1996, Moghetti et al. 2000).
Finasteride, a 5α-reductase inhibitor, inhibits the conversion of T to DHT, the active androgen in the hair follicle (Rittmaster 1997). It is administered 5 mg daily in the treatment of hirsutism and seems to be as effective as flutamide (Erenus et al. 1997, Falsetti et al. 1997, Sahin et al. 1998). Combined with OC including CPA, finasteride significantly decreased the hirsutism score after 3 months of treatment, while OC alone induced this effect after 6 months of treatment (Tartagni et al. 2000).
The antifungal agent ketoconazole seems to be an effective antiandrogen in the treatment of hirsutism in PCOS women using a dose of 400 mg daily (Gokmen et al. 1996). It is a known inhibitor of steroidogenic enzymes of the P450 family (Feldman 1986).
All the medications above may have teratogenic effects. It is therefore suggested that these medications should be used with a proper contraception, usually OC, in women who are sexually active (Taylor 1998).
When infertility is not an issue, the treatment of irregular menstruation is best achieved using a low-dose OC or by the cyclic administration of oral progestins. Progestin therapy improves irregular menstrual bleeding and reduces the risk of endometrial cancer (Dahlgren & Janson 1994a). The most conservative approach with progestins is to induce bleeding monthly (Taylor 1998). A low dose OC normalizes menstrual cycles as well as prevents endometrial hyperplasia (Hulka et al. 1982). It also suppresses hirsutism and provides contraception in addition to its other known benefits. There is conflicting data as to whether or not the treatment with OCs increases insulin resistance. Some data exists suggesting a worsening in carbohydrate tolerance (Morin-Papunen et al. 2000) and enhanced insulin resistance in women who receive OC (Godsland et al. 1992, Korytkowski et al. 1995), although OC seemed not to be associated with an adverse effect on the lipid profile of PCOS women.
The first-line treatment for the induction of ovulation in PCOS women with infertility is the antiestrogen clomiphene citrate (CC). The ovulation rate is high (75-80%) with a cumulative conception rate approaching normal (Franks et al. 1985, Hull 1992). There is some evidence that combining dexamethasone to CC to suppress adrenal androgen secretion increased ovulation and pregnancy rates in PCOS women with elevated DHEAS or resistance to CC (Lobo et al. 1982, Daly et al. 1984, Trott et al. 1996). CC has been shown to reduce plasma IGF-1 concentrations and increase serum SHBG and plasma IGFBP-1 concentrations (Bützow T et al. 1995, De Leo et al. 2000).
Approximately 20-25% of women with PCOS are, however, resistant to clomiphene. For these women, the induction of ovulation is performed with the exogenous administration of gonadotrophin preparations, either with or without GnRHa to inhibit endogenous ovarian function, with a 50% cumulative pregnancy rate (Wang & Gemzell 1980). As the risk of ovarian hyperstimulation in response to exogenous gonadotrophins is greater in women with PCOS, these women are good candidates for in vitro fertilization (IVF) techniques (Taylor 1998). In PCOS associated with hypersecretion of LH, purified FSH preparations have theoretical advantages over the use of hMG preparations containing both FSH and LH. It remains uncertain whether or not this claimed advantage extends into clinical practice. Clinical results (including pregnancy rate) in IVF cycles have been similar in PCOS women using purified or recombinant FSH compared with PCOS women using hMG preparations (Homburg et al. 1990, Sagle et al. 1991, Fulghesu et al. 1992, Teissier et al. 1999).
Surgical treatment by bilateral wedge resection, although relatively succesful in restoring ovulation, has fallen from grace due to its propensity for adhesion formation (Buttram & Vaquero 1975, Adashi et al. 1981). Laparoscopic ovarian diathermy was introduced by Gjönnaes (Gjönnaess 1984). In his small study and in larger studies since (Aakvaag & Gjönnaess 1985, Kovacs et al. 1991, Naether et al. 1993a, Felemban et al. 2000) ovulation rates of 70-90% and cumulative pregnancy rates of 40-70% have been achieved. Postoperative laparoscopy has revealed the presence of mild intraperitoneal adhesions in about 20% of these cases (Dabirashrafi et al. 1991, Naether & Fischer 1993b). A case of unilateral ovarian atrophy has been reported after the procedure (Dabirashrafi 1989). The benefit of ovarian diathermy is limited to approximately 6 months, but it is a promising mode of therapy for clomiphen resistant women with PCOS and large ovaries. It was recently shown that laparoscopic ovarian drilling with an insulated needle cautery is an effective treatment in clompihen resistant women with PCOS. This treatment was associated with a minimal amount of adhesion formation (Felemban et al. 2000).
In numerous studies of women with PCOS, caloric restriction (even without weight loss) or weight-reducing diets have resulted in a normalization of insulin sensitivity. The improvement in endocrine-metabolic parameters occurs after 4 to 12 weeks of dietary restriction (Kiddy et al. 1992), an increase in SHBG is accompanied by a fall in free T, insulin and IGF-I levels. Serum concentrations of IGFBP-1 rise significantly (Hamilton-Fairley et al. 1993). Consequent to these changes, weight loss is attended by a reduction of hyperandrogenism and a restoration of ovulation (Bates & Whitworth 1982) (Harlass et al. 1984, Jakubowicz & Nestler 1997). Hirsutism also appears to improve significantly in most of the patients losing weight (Pasquali et al. 1989).
Weight loss may also decrease the LH pulse amplitude (Harlass et al. 1984). It has been demonstrated in severly overweight infertility patients that weight reduction with a very low calorie diet results in a decrease in LH concentrations, a reduction in the LH/FSH ratio, and FSH predominance favoring folliculogenesis. The decrease in LH concentrations was inversely related to the severity of insulin resistance (Butzow et al. 2000).
Moderate exercise, a process of increased fuel expenditure, has been shown to induce a rise in serum IGFBP-1 with a decrease in serum IGF-I concentrations (Suikkari et al. 1989). Thus, when combined with dietary restriction, exercise serves as an important adjunct therapy for PCOS (Yen 1999).
The first anti-diabetic drugs studied in PCOS women were diazoxide and the somatostatin analogue, octreotide, which can both directly inhibit pancreatic insulin secretion. They also reduce serum androgen and LH concentrations. Octreotide has been shown to restore ovulation (Nestler et al. 1989, Prelevic et al. 1995). The long-term use of these drugs may, however, worsen glucose tolerance and further increase the risk of developing diabetes (Lillioja et al. 1993, Dunaif 1995a).
The demonstration of β -endorphins in the human pancreas (Ipp et al. 1978) and the evidence that they may stimulate insulin and glucagon release in humans (Giugliano et al. 1987) suggest that opioids may play a role in glycoregulation. The opioid antagonist naltrexone has been demonstrated to decrease insulin response during OGTT and may do so largely by increasing the rate of insulin clearance (Lanzone et al. 1991, Lanzone et al. 1995b, Fulghesu et al. 1998). Opioid antagonists do not seem to affect glucose utilization during a clamp study (Fulghesu et al. 1998). Although these antagonists have not been associated with a lowering of LH or androgens (Fulghesu et al. 1993, Cagnacci et al. 1994), they appear to reduce the LH response to the GnRH test in hyperinsulinemic patients (Lanzone et al. 1995b). Improvements in both spontaneous ovulation and responsiveness to CC have also been noted in association with the decline in circulating insulin (Roozenburg et al. 1997).
The biguanide molecule was first synthesized in 1879. Metformin and phenphormin, the two main biguanides, were introduced in the 1920s (Bailey & Nattrass 1988). Metformin (dimethylbiguanide) is approved for the treatment of type 2 DM and is in use worldwide. Although it is not technically considered an “insulin sensitizer”, meformin has several mechanisms of action which tend to result in improvements in hyperinsulinemia. It has been suggested that metformin should be regarded as an “antihyperglycemic” agent (Bailey & Nattrass 1988). The effect is seen in the liver where it suppresses hepatic glucose output, possibly due to an inhibition of gluconeogenesis (Stumvoll et al. 1995) secondarily to the decrease in serum FFA levels (Perriello et al. 1994, Wiesenthal et al. 1999). It has also been suggested that metformin decreases FFA uptake and oxidation in the liver and muscle and improves insulin-mediated glucose utilization in these tissues via a substrate-competition effect (Randle et al. 1963, Abbasi et al. 1997, Abbasi et al. 1998). There are studies, however, in which no effect of metformin on hepatic glucose production was observed (Riccio et al. 1991, Abbasi et al. 1997). In vivo, metformin appears to delay glucose absorption and increase glucose utilization by the intestine (Bailey & Turner 1996). Metformin may also improve peripheral insulin resistance (Inzucchi et al. 1998).
In vitro and in vivo evidence exists according to which metformin improves insulin action and direct effects on glucose utilization in lymphocytes or adipocytes (Nosadini et al. 1987, Purrello et al. 1987, Matthaei et al. 1991). Metformin is shown to increase insulin-mediated glucose uptake in peripheral tissues with predominantly enhanced nonoxidative (Riccio et al. 1991, Widen et al. 1992, Bell & Hadden 1997) or oxidative glucose metabolism (Perriello et al. 1994). Others have failed to confirm these results (Wu et al. 1990). It is possible that meformin improves insulin-receptor binding in vitro by increasing the number of low-affinity insulin binding sites in lymphocytes, erythrocytes and human breast cells (Holle et al. 1981, Bailey & Nattrass 1988). Metformin could also potentiate insulin action by postreceptor effects, as demonstrated by an increase in both glycogen synthesis and glucose oxidation in the soleus muscle of mice (Bailey et al. 1986). A possible postreceptor mechanism has not been defined. Metformin may inhibit lipolysis in adipose tissue and decrease both FFA concentrations and lipid oxidation (Riccio et al. 1991, Perriello et al. 1994, Abbasi et al. 1998). Metformin significantly reduces circulating lipid levels because of a reduced hepatic synthesis of very low-density lipoprotein (VLDL) and Trigly (Fedele et al. 1976). Decreases in plasma Trigly, total and LDL cholesterol concentrations and increases in HDL and the HDL/LDL cholesterol ratio, independently of improved glycemic control, have been observed (DeFronzo & Goodman 1995).
Velasquez published the first study of metformin (1.5 g daily) in women with PCOS (Velazquez et al. 1994), demonstrating an improvement in T and free T levels in obese patients. Subsequent studies have demonstrated that metformin (1.0 to 2.25 g daily) can increase SHBG levels and reduce free T levels (Nestler & Jakubowicz 1996), improve ovulation rates (Velazquez et al. 1997, Morin-Papunen et al. 1998, Moghetti et al. 2000) and improve response to CC (Nestler et al. 1998b) or exogenous gonadotropins (De Leo et al. 1999). It has recently been reported that metformin (1275 mg daily for 6 months) reduced hyperinsulinemia, hirsutism and hyperandrogenism, and restored eumenorrhea for the time of the treatment in nonobese adolescent girls with a history of precocious pubarche who had a tendency to hyperinsulinism (Ibanez et al. 2000). It has been shown that insulin reduction with metformin increases follicular and luteal phase serum glycodelin and IGFBP-1 concentrations and enhances luteal phase uterine vascularity and blood flow in PCOS. It was concluded that these changes may reflect an improved endometrial milieu for the establishment and maintenance of pregnancy (Jakubowicz et al. 2001). Not all studies, however, have demonstrated a benefit of this medication (Crave et al. 1995, Ehrmann et al. 1997a).
The androgen lowering effects of metformin are still unclear. In general, studies in which metformin therapy results in a reduction in serum insulin concentrations are the same studies, which demonstrate a significant decrease in serum T concentrations (Taylor 2000a). Androgen responses to ACTH have been demonstrated to decrease after 4 weeks of metformin (1-1.5 g daily) treatment (la Marca et al. 1999) or not change after 12 weeks of metformin treatment (Unluhizarci et al. 1999a). Studies evaluating the ovarian androgen response to leuprolide acetate, buserelin or to hCG have shown either decreased (Nestler & Jakubowicz 1996, la Marca et al. 2000) or unchanged ovarian androgen response after 4 to 12 weeks of metformin (1-1.5 g daily) treatment (Unluhizarci et al. 1999b). In a recent randomized, double-blind and placebo-controlled 6-month trial in PCOS women with abdominal obesity, it was shown that long-term treatment with metformin (1.7 g daily) added to a hypocaloric diet induced (in comparison with placebo) a greater reduction of body weight and abdominal fat and a more consistent decrease of serum insulin, T, and leptin concentrations. These changes were associated with a more significant improvement of hirsutism and menstrual irregularities. In that study, metformin significantly decreased insulin and the C-peptide response to oral glucose administration, which indicates a contemporary improvement of both insulin resistance and β -cell function (Pasquali et al. 2000). It is difficult to explain why metformin succesfully lowers insulin and androgen levels in some studies but not in others. Variations in body weight, dosing, entry criteria or genetic background may be the explanation (Taylor 2000a).
The thiazolidinediones are true “insulin sensitiziers” which improve peripheral glucose uptake, while also having some effect on hepatic glucose production (Inzucchi et al. 1998). To date, five studies exist documenting the efficacy of troglitazone, the first-generation thiazolidinedione in obese women with PCOS (Dunaif et al. 1996b, Ehrmann et al. 1997b, Hasegawa et al. 1999, Mitwally et al. 1999, Azziz et al. 2001). Troglitazone improves the action of insulin in the liver, skeletal muscle, and adipose tissue directly. It acts primarily as a ligand for the nuclear peroxisome proliferator activated receptor, which, when activated, enhances the transcription of factors promoting glucose disposal, primarily in the muscle (Saltiel & Olefsky 1996b).
All of the studies examining the effect of troglitazone (150-600 mg for 12-14 weeks) on PCOS women have demonstrated a reduction in fasting insulin levels or the insulin area under the curve in OGTT, as well as a reduction in free T levels without a change in body weight (Dunaif et al. 1996b, Ehrmann et al. 1997b, Hasegawa et al. 1999 Azziz et al. 2001). Troglitazone suppresses ovarian androgen response to leuprolide acetate and reduces the functional activity of PAI-1 in blood (Ehrmann et al. 1997b). Although troglitazone seems effective in these studies of women with PCOS, reports of fatal hepatotoxicity have significantly limited its usefulness. A large multicenter study of troglitazone showed improvement of ovulation and hirsutism in women with PCOS (Azziz et al. 2001). According to its package insert, troglitazone reduces serum levels of ethinyl estradiol and norethindrone by approximately 30% each. Therefore, women with PCOS using OCs might experience contraceptive failure or breakthrough bleeding (Taylor 2000a). There are two new thiazolidinediones approved for use for type 2 DM in USA, rosiglitazone and pioglitazone, which are theoretically attractive alternatives to troglitazone due to their apparently reduced risk of hepatotoxicity. However, no published reports are available for these drugs in the treatment of PCOS (Taylor 2000a).
The medication most recently studied in women with PCOS is d-chiro-inositol, a naturally-occurring substance which seems to improve insulin action by increasing insulin signal transduction at the postreceptor level. When insulin binds to its receptor, inositol phosphoglycan mediators are generated by hydrolysis of glycosylphosphatidylinositol lipids located at the cell membrane. An inositol phosphoglycan molecule containing d-chiro-inositol and galactosamine is known to play a role in activating key enzymes controlling the oxidative and nonoxidative metabolism of glucose (Ortmeyer et al. 1993). In 20 obese women with PCOS, d-chiro-inositol (1200 mg) improved serum insulin and serum androgen concentrations, decreased WHR and improved ovulation (Nestler et al. 1999).