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Resumption of fertility with diet in overweight women
RBMOnline - Vol 5. No 1. 60–64 Reproductive BioMedicine Online; www.rbmonline.com/Article/618 on web 15 May 2002
Reviews Resumption of fertility with diet in overweight women Pier Giorgio Crosignani is Professor in Obstetrics and Gynecology and Chairman at the University of Milano and is a past-Chairman of the European Society of Human Reproduction (ESHRE, 1989–1991). He is also organizer of the annual ESHRE Capri Workshops on Reproductive Medicine. He has served in the past or is at the present on the Editorial Board of Contraception, Fertility and Sterility, Gynecologic and Obstetric Investigation, Human Reproduction, International Journal of Fertility, Journal of Assisted Reproduction and Genetics, Maturitas and the Middle East Fertility Society Journal. Professor Crosignani’s current research interests include infertility, contraception and the menopause. Dr Pier Giorgio Crosignani Pier Giorgio Crosignani1, Walter Vegetti, Michela Colombo, Guido Ragni First Department of Obstetrics and Gynaecology, University of Milan, Via della Commenda 12, 20122 Milan, Italy 1Correspondence: Tel: +39 02 57992256; Fax: +39 02 55187146; e-mail: [email protected]
Abstract In young women being overweight appears to be one of the major and still neglected causes of subfertility. Not only the excessive amount but also the distribution of body fat is clearly related to loss of fertility. The mechanism through which obesity impairs ovulation and fertility is largely unknown, but it is well known that being overweight lowers the concentration of sex hormone binding globulin and increases androgen and insulin secretion and insulin resistance. These high concentrations of androgen and insulin in turn are important factors in the preferential abnormal localization of body fat. In addition, ovulation induction or ovarian stimulation in overweight women is a not easy task, since these patients are often unresponsive to the stimulatory drugs and, in addition, have a higher rate of miscarriages. Weight reduction improves these patients’ biochemical indices and fertility rates. The spontaneous pregnancy rate can be expected to be around 30%, but an additional 40–50% drug-induced pregnancy rate can be achieved with a 10–15% weight loss. Drugs increasing insulin sensitivity also improve spontaneous ovulation and fertility in obese women but still need to be tested in larger controlled trials. In conclusion, appropriate counselling about weight reduction through diets and exercise can restore both health and fertility, avoiding much frustration, and saving time and money. Keywords: anovulation, fertility, metformin, obesity, ovarian drilling
Introduction The negative prognostic value for spontaneous conception of the duration of infertility and older age is well known, but the negative effect of a woman’s obesity on the couple’s fecundity is still underestimated. This review evaluates evidence from the literature regarding the influence of obesity or being overweight on spontaneous and induced fertility, with a view to documenting the positive effect of weight reduction.
Effect of obesity on ovulation and spontaneous fertility A negative effect of obesity on fertility was first noted 2500 years ago (Hippocrates, 1976). In more modern times, Reid et al. (1987) noted that obesity and overweight were associated with menstrual irregularities, anovulation, polycystic ovary syndrome (PCOS) and infertility.
60
An epidemiological study published in 1994, covering 597 cases and 1695 controls, investigated the relationship between body mass index (BMI) and anovulatory infertility (Grodstein et al., 1994). In this study, obese women (BMI >27) had a higher relative risk (RR) of anovulatory infertility than women with lower BMI (Table 1). The risk of infertility increased more among the 113 overweight women with PCOS, but was still elevated among overweight patients after excluding this subgroup of patients [RR = 2.0; 95% confidence interval (CI) = 1.4–3.0]. In women, a BMI of >27 kg/m2 today is considered to be a factor for decreased fertility (Barbieri, 2001). Not only the excessive amount but also the distribution of body fat is clearly related to irregular menstrual cycles, oligomenorrhoea, hirsutism (Hartz et al., 1984) and fecundity. Four hundred and eighty-nine women who participated in a donor insemination programme were divided according to
Reviews - Resumption of fertility in overweight women - PG Crosignani et al.
Table 1. Relative risk of primary ovulatory infertility according to BMI (modified from Grodstein et al., 1994). BMI
Number (%) Cases
<17
RR
95% CI
Controls
9 (1.5)
16 (0.9)
1.6
0.7–3.9
17–19.9
68 (11.3)
588 (15.3)
0.7
0.6–0.9
20–24.9a
326 (54.6)
942 (55.6)
1.0
25–26.9
31 (5.2)
73 (4.3)
1.2
0.8–1.9
≥27
86 (14.4)
80 (4.7)
3.1
2.2–4.4
aWomen with BMI 20–24.9 were used as the reference group.
their body fat distribution and their cumulative pregnancy rates were calculated (Zaadstra et al., 1993). The pregnancy rate was highest in women with a waist to hip ratio less than 0.8 (‘pear’ shape) (Zaadstra et al., 1993). Central obesity measured by an increased waist to hip ratio (‘apple’ shape) was significantly associated with a lower probability of conception per cycle (Figure 1). In addition, obesity is associated with an increased rate of miscarriage in women with PCOS, and those with normal ovarian morphology (Pettigrew and HamiltonFairley, 1997). The harmful effect has also been observed in pregnancies obtained through IVF or after intracytoplasmic sperm injection (ICSI) (Fedorcsak et al., 2000). The mechanism through which obesity impairs fertility is largely unknown. However, being overweight is known to reduce sex hormone binding globulin (SHBG) concentrations (Kiddy et al., 1990) and increase insulin secretion and insulin resistance (Barbieri et al., 1988; Nestler et al., 1989). Weight loss in obese women after gastroplasty quickly restores normal insulin secretion, clearance and action on glucose metabolism (Letiexhe et al., 1995). Insulin plays a complex role, since it stimulates androgen secretion and, together with androgens, influences the pattern of body fat distribution in premenopausal women (Sharp et al., 1991). This relationship was clearly shown in a study by Pasquali et al. (1991). Five groups of women were investigated: group 1 consisted of 14 normal weight, eumenorrhoeic women; group 2 of nine obese eumenorrhoeic women; group 3 of 14 normal weight, hyperandrogenic women with PCOS; group 4 of 10 obese hyperandrogenic women with PCOS; finally, group 5 comprised 10 obese hyperandrogenic women with PCOS and acanthosis nigricans. As expected, the study found that fasting and glucose-stimulated insulin concentrations were significantly higher in all obese patients, and especially in those with hyperandrogenism; in addition, body fat distribution, expressed by the waist to hip ratio, showed progressively higher values (P < 0.01) from normal to obese women, to hyperandrogenic, to obese hyperandrogenic women, and was particularly high in obese hyperandrogenic women with acanthosis nigricans (Pasquali et al., 1991). Therefore the authors suggested that both hyperinsulinaemia and androgens are important factors in the preferential abdominal localization of body fat. Leptin is a protein hormone secreted by adipocytes under the control of the obese (ob) gene, is primarily involved in the
Figure 1. Cumulative pregnancy rate in 489 women having artificial insemination according to waist–hip ratio (277 women had a ratio <0.8 and 21 a ratio ≥0.8) (from Zaadstra et al., 1993, with permission from the BMJ Publishing Group). Kaplan-Meyer log rank P = 0.0085. regulation of energy metabolism and appears to influence several reproductive functions (Chehab et al., 1996). In women, higher leptin concentrations are associated with an earlier menarche (Matkovic et al., 1997), while decreased serum leptin concentrations have been associated with the improved ovarian function induced by insulin sensitizing therapy in PCOS obese patients (Morin-Papunen et al., 1998a).
Effect of obesity on pharmacologically induced cycles The anovulatory overweight patient is a frequent challenge for the reproductive endocrinologist and the excessive body weight can make induction of ovulation or ovarian stimulation for assisted reproduction very difficult. Obese patients are often unresponsive to clomiphene citrate ovulation induction (Imani et al., 1998) and the dose required to achieve ovulation in obese normogonadotrophic anovulatory patients is higher if they are overweight (Shepard et al., 1979; Lobo et al., 1982). Similarly, induction of ovulation using pulsatile gonadotrophin-releasing hormone is far less successful in overweight patients, as shown in two independent studies (Homburg et al., 1989; Filicori et al., 1994). Overweight patients with and without PCOS treated with low-dose gonadotrophins had lower ovulation rates and higher miscarriage rates (Hamilton-Fairley et al., 1992). Insulin resistance has been suggested to be the main causative mechanism associated with excessive body weight (Dale et al., 1998). Overweight women also have a suboptimal ovarian response to gonadotrophins in IVF and ICSI cycles. Ovarian responsiveness was studied in 111 patients in an IVF programme; the number of follicles (10 mm obtained after 4 days of stimulation with human menopausal gonadotrophin) and the number of oocytes retrieved were significantly lower in patients in the upper tertiles of BMI (Crosignani et al., 1994). These data have now been confirmed in a larger series of IVF and ICSI patients (Perotti et al., 1999). Moreover, in
61
Reviews - Resumption of fertility in overweight women - PG Crosignani et al.
Table 2. Weight loss, pregnancy rate and abortion rate in two groups of overweight patients (modified from Clark et al., 2000). Group A = conventional treatment, group B = support group programme.
Weight loss (kg after 6 months) Pregnancies after 18 months (n (%)) Early pregnancy losses (n (%))
Group A (n = 84)
Group B (n = 87)
1.3
4.7a
18 (21.4)
53 (60.9)b
3 (16.6)
6 (11.3)
aP = 0.001. bSupport group programme: group session programme including diet, exercise and psychological support.
obese PCOS patients there is a higher risk of ovarian hyperstimulation syndrome and multiple pregnancy using conventional gonadotrophin treatment or assisted reproduction techniques (Franks, 1995).
Overweight women: pro-fertility effect of weight reduction Weight reduction can change the picture. Weight loss can improve menstrual cycle rhythm, ovulation, fertility and, in PCOS patients, it can reduce hirsutism, hyperandrogenaemia and insulin resistance. In 1995 and 1998, Clark et al. demonstrated that weight loss is able to re-establish ovulation in obese anovulatory patients or to improve their response to ovulation induction. In a series of 67 anovulatory women, 90% resumed ovulation after weight loss, 78% conceived (33% spontaneously) and 67% achieved a live birth (Clark et al., 1998). These data have now been reconfirmed in a larger number of patients in a study maximizing weight loss through exercise and psychological support (Table 2) (Clark et al., 2000). In another study on obese, non-PCOS patients, weight loss resulted in a significant reduction in blood glucose, insulin, androstenedione, dihydrotestosterone and oestradiol
concentrations (Hollmann et al., 1996). These effects were even more evident in obese PCOS patients (Lefebvre et al., 1997; Pasquali et al., 1997). In these women, weight loss reduces circulating androgens and raises SHBG (Kiddy et al., 1990), enhances insulin sensitivity (Guzick et al., 1994; Andersen et al., 1995; Holte et al., 1995; Huber-Bucholz et al., 1999) and consistently improves menstrual cyclicity and fertility rates (Bates and Whitworth, 1982; Pasquali et al., 1989, Franks et al., 1991). Anthropometric indices in young overweight women while dieting show a critical change of body fat distribution with a lower waist to hip ratio and loss of fat mass (Table 3) (Crosignani et al., 1999). Ovarian morphology also changes, with a significant reduction in volume (Crosignani, unpublished data). In this series, among the 21 out of 26 patients with irregular menstrual cycles who lost weight, 15 re-established regular cycles (71%). Of the 26 patients with anovulation before dietary treatment, 69% of the serum progesterone assessments performed during the diet showed ovulatory values. During a study period of 6 months, eight spontaneous pregnancies were obtained in the 26 patients who lost weight (31% pregnancy rate per patient). Neither menstrual cycle improvement nor ovulatory values of progesterone, and no pregnancies were obtained in the 12 patients who did not lose weight (Crosignani et al., 1999).
Metformin Because of the role of insulin resistance in promoting anovulation in obese patients, insulin sensitizing agents have been employed with the aim of restoring spontaneous ovulation and fertility in obese PCOS patients. Metformin, a biguanide that improves the action of insulin at the cellular level without affecting insulin secretion (Barley et al., 1996), appears very promising. In a study of 22 oligo/amenorrhoeic PCOS patients who underwent a 6-month course with 500 mg metformin three times a day, 21 (95.7%) showed a restoration of menstrual cycles and four (19%) became pregnant. This was accompanied by a reduction in LH and free testosterone serum concentrations (Velazquez et al., 1997). In another study of 61 obese PCOS patients, metformin was compared with placebo: metformin significantly lowered the serum insulin response to oral glucose. Moreover, patients treated with metformin showed marked increases in both spontaneous and clomiphene-induced ovulation (Nestler et al., 1998). In a third
Table 3. Body fat distribution and anthropometric indexes before and during dietary treatment (Crosignani et al., 1999). Basal (26 patients and controls)
5% weight loss (18 patients)
10% weight loss (10 patients)
80.6 ± 0.7
75.0 ± 9.0a
68.9 ± 8.2a
Body mass index (kg/m2) 31.7 ± 4.3
29.5 ± 4.5a
27.1 ± 3.4a 31.7 ± 3.0b 0.83 ± 0.05a
Weight (kg)
62
Arm muscle area
33.3 ± 3.0
32.6 ±
3.0a
Waist–hip ratio
0.89 ± 0.06
0.87 ±
0.06a
Total body water (l)
35.8 ± 2.6
35.8 ± 3.4
Free fat mass (kg)
46.8 ± 3.3
46.5 ± 4.0
45.2 ± 2.5
Fat mass (kg)
33.8 ± 6.9
29.7 ± 7.5a
23.8 ± 6.8a
aP < 0.001; bP < 0.05 versus basal values (t-test for paired data).
34.6 ± 3.3
Reviews - Resumption of fertility in overweight women - PG Crosignani et al.
study of 20 obese PCOS patients, these data were confirmed by a reduction in mean testosterone and leptin concentrations and more regular menstrual cycles during therapy (MorinPapunen et al., 1998a,b). Pasquali et al. (2000) showed that long-term treatment with metformin in obese women is associated with a consistent reduction of abdominal fat and lowered concentrations of serum insulin, testosterone and leptin. These changes were more pronounced in patients with PCOS. Similar endocrine changes associated with a 23% ovulation rate have been recently reported in a large placebo controlled study in anovulatory women with oligomenorrhoea and/or PCOS (Fleming et al., 2002). Interestingly, it appears that metformin can improve hyperinsulinaemia and insulin sensitivity independently of changes in body weight (Glueck et al., 1999; Moghetti et al., 2000). In addition, metformin decreases androgen production in human theca cells (Attia et al., 2001). Nevertheless co-administration of metformin during gonadotrophin treatment in PCOS patients resistant to clomiphene citrate did not improve the clinical outcome in all studies (Stadtmauer et al., 2001; Yarali et al., 2002). Metformin administration during pregnancy to women with PCOS seems to reduce the first-trimester pregnancy loss (Jakubowicz et al., 2002) and the risk of gestational diabetes in hyperinsulinaemic patients (A. Lanzone, personal communication).
Laparoscopic ovarian electrocautery In the last 10 years, laparoscopic ovarian electrocautery (ovarian drilling) has been widely used as a nonpharmacological method of inducing ovulation. The mechanism underlying the electrocautery procedure is not yet known, but it has been shown that after the treatment there is a consistent decrease in peripheral androgen concentrations with a subsequent decline in LH (Aakvaag and Gjonnaess, 1985). These changes are not accompanied by a parallel improvement in insulin sensitivity (Lemieux et al., 1999). Transvaginal ovarian drilling with hydrolaparoscopy appears an interesting alternative to the more invasive laparoscopic approach (Fernandez et al., 2001). Again, the rate of ovulation obtained after this treatment is significantly lower in obese patients (Gjonnaess, 1994; Liguori et al., 1996).
Conclusions Being overweight in itself can cause normogonadotrophic anovulation, interfering in the normal ovulatory mechanism. Considering its prevalence among women of reproductive age, overweight appears to be one of the major and still neglected causes of infertility. Being overweight may also aggravate existing chronic anovulation linked to PCOS. Moreover, overweight patients show high rates of early miscarriage and are less responsive both to ovulation induction and to ovarian stimulation for assisted reproduction techniques. Appropriate counselling to encourage weight loss through dieting and exercise can help restore spontaneous fertility or improve the results of pro-fertility treatments, avoiding frustration and disappointment and saving time and money. Besides helping re-establish fecundity, this strategy is also likely to improve the woman’s overall health. Pharmacological agents to increase insulin sensitivity, although promising, need to be tested in larger controlled studies.
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Reviews Resumption of fertility with diet in overweight women Pier Giorgio Crosignani is Professor in Obstetrics and Gynecology and Chairman at the University of Milano and is a past-Chairman of the European Society of Human Reproduction (ESHRE, 1989–1991). He is also organizer of the annual ESHRE Capri Workshops on Reproductive Medicine. He has served in the past or is at the present on the Editorial Board of Contraception, Fertility and Sterility, Gynecologic and Obstetric Investigation, Human Reproduction, International Journal of Fertility, Journal of Assisted Reproduction and Genetics, Maturitas and the Middle East Fertility Society Journal. Professor Crosignani’s current research interests include infertility, contraception and the menopause. Dr Pier Giorgio Crosignani Pier Giorgio Crosignani1, Walter Vegetti, Michela Colombo, Guido Ragni First Department of Obstetrics and Gynaecology, University of Milan, Via della Commenda 12, 20122 Milan, Italy 1Correspondence: Tel: +39 02 57992256; Fax: +39 02 55187146; e-mail: [email protected]
Abstract In young women being overweight appears to be one of the major and still neglected causes of subfertility. Not only the excessive amount but also the distribution of body fat is clearly related to loss of fertility. The mechanism through which obesity impairs ovulation and fertility is largely unknown, but it is well known that being overweight lowers the concentration of sex hormone binding globulin and increases androgen and insulin secretion and insulin resistance. These high concentrations of androgen and insulin in turn are important factors in the preferential abnormal localization of body fat. In addition, ovulation induction or ovarian stimulation in overweight women is a not easy task, since these patients are often unresponsive to the stimulatory drugs and, in addition, have a higher rate of miscarriages. Weight reduction improves these patients’ biochemical indices and fertility rates. The spontaneous pregnancy rate can be expected to be around 30%, but an additional 40–50% drug-induced pregnancy rate can be achieved with a 10–15% weight loss. Drugs increasing insulin sensitivity also improve spontaneous ovulation and fertility in obese women but still need to be tested in larger controlled trials. In conclusion, appropriate counselling about weight reduction through diets and exercise can restore both health and fertility, avoiding much frustration, and saving time and money. Keywords: anovulation, fertility, metformin, obesity, ovarian drilling
Introduction The negative prognostic value for spontaneous conception of the duration of infertility and older age is well known, but the negative effect of a woman’s obesity on the couple’s fecundity is still underestimated. This review evaluates evidence from the literature regarding the influence of obesity or being overweight on spontaneous and induced fertility, with a view to documenting the positive effect of weight reduction.
Effect of obesity on ovulation and spontaneous fertility A negative effect of obesity on fertility was first noted 2500 years ago (Hippocrates, 1976). In more modern times, Reid et al. (1987) noted that obesity and overweight were associated with menstrual irregularities, anovulation, polycystic ovary syndrome (PCOS) and infertility.
60
An epidemiological study published in 1994, covering 597 cases and 1695 controls, investigated the relationship between body mass index (BMI) and anovulatory infertility (Grodstein et al., 1994). In this study, obese women (BMI >27) had a higher relative risk (RR) of anovulatory infertility than women with lower BMI (Table 1). The risk of infertility increased more among the 113 overweight women with PCOS, but was still elevated among overweight patients after excluding this subgroup of patients [RR = 2.0; 95% confidence interval (CI) = 1.4–3.0]. In women, a BMI of >27 kg/m2 today is considered to be a factor for decreased fertility (Barbieri, 2001). Not only the excessive amount but also the distribution of body fat is clearly related to irregular menstrual cycles, oligomenorrhoea, hirsutism (Hartz et al., 1984) and fecundity. Four hundred and eighty-nine women who participated in a donor insemination programme were divided according to
Reviews - Resumption of fertility in overweight women - PG Crosignani et al.
Table 1. Relative risk of primary ovulatory infertility according to BMI (modified from Grodstein et al., 1994). BMI
Number (%) Cases
<17
RR
95% CI
Controls
9 (1.5)
16 (0.9)
1.6
0.7–3.9
17–19.9
68 (11.3)
588 (15.3)
0.7
0.6–0.9
20–24.9a
326 (54.6)
942 (55.6)
1.0
25–26.9
31 (5.2)
73 (4.3)
1.2
0.8–1.9
≥27
86 (14.4)
80 (4.7)
3.1
2.2–4.4
aWomen with BMI 20–24.9 were used as the reference group.
their body fat distribution and their cumulative pregnancy rates were calculated (Zaadstra et al., 1993). The pregnancy rate was highest in women with a waist to hip ratio less than 0.8 (‘pear’ shape) (Zaadstra et al., 1993). Central obesity measured by an increased waist to hip ratio (‘apple’ shape) was significantly associated with a lower probability of conception per cycle (Figure 1). In addition, obesity is associated with an increased rate of miscarriage in women with PCOS, and those with normal ovarian morphology (Pettigrew and HamiltonFairley, 1997). The harmful effect has also been observed in pregnancies obtained through IVF or after intracytoplasmic sperm injection (ICSI) (Fedorcsak et al., 2000). The mechanism through which obesity impairs fertility is largely unknown. However, being overweight is known to reduce sex hormone binding globulin (SHBG) concentrations (Kiddy et al., 1990) and increase insulin secretion and insulin resistance (Barbieri et al., 1988; Nestler et al., 1989). Weight loss in obese women after gastroplasty quickly restores normal insulin secretion, clearance and action on glucose metabolism (Letiexhe et al., 1995). Insulin plays a complex role, since it stimulates androgen secretion and, together with androgens, influences the pattern of body fat distribution in premenopausal women (Sharp et al., 1991). This relationship was clearly shown in a study by Pasquali et al. (1991). Five groups of women were investigated: group 1 consisted of 14 normal weight, eumenorrhoeic women; group 2 of nine obese eumenorrhoeic women; group 3 of 14 normal weight, hyperandrogenic women with PCOS; group 4 of 10 obese hyperandrogenic women with PCOS; finally, group 5 comprised 10 obese hyperandrogenic women with PCOS and acanthosis nigricans. As expected, the study found that fasting and glucose-stimulated insulin concentrations were significantly higher in all obese patients, and especially in those with hyperandrogenism; in addition, body fat distribution, expressed by the waist to hip ratio, showed progressively higher values (P < 0.01) from normal to obese women, to hyperandrogenic, to obese hyperandrogenic women, and was particularly high in obese hyperandrogenic women with acanthosis nigricans (Pasquali et al., 1991). Therefore the authors suggested that both hyperinsulinaemia and androgens are important factors in the preferential abdominal localization of body fat. Leptin is a protein hormone secreted by adipocytes under the control of the obese (ob) gene, is primarily involved in the
Figure 1. Cumulative pregnancy rate in 489 women having artificial insemination according to waist–hip ratio (277 women had a ratio <0.8 and 21 a ratio ≥0.8) (from Zaadstra et al., 1993, with permission from the BMJ Publishing Group). Kaplan-Meyer log rank P = 0.0085. regulation of energy metabolism and appears to influence several reproductive functions (Chehab et al., 1996). In women, higher leptin concentrations are associated with an earlier menarche (Matkovic et al., 1997), while decreased serum leptin concentrations have been associated with the improved ovarian function induced by insulin sensitizing therapy in PCOS obese patients (Morin-Papunen et al., 1998a).
Effect of obesity on pharmacologically induced cycles The anovulatory overweight patient is a frequent challenge for the reproductive endocrinologist and the excessive body weight can make induction of ovulation or ovarian stimulation for assisted reproduction very difficult. Obese patients are often unresponsive to clomiphene citrate ovulation induction (Imani et al., 1998) and the dose required to achieve ovulation in obese normogonadotrophic anovulatory patients is higher if they are overweight (Shepard et al., 1979; Lobo et al., 1982). Similarly, induction of ovulation using pulsatile gonadotrophin-releasing hormone is far less successful in overweight patients, as shown in two independent studies (Homburg et al., 1989; Filicori et al., 1994). Overweight patients with and without PCOS treated with low-dose gonadotrophins had lower ovulation rates and higher miscarriage rates (Hamilton-Fairley et al., 1992). Insulin resistance has been suggested to be the main causative mechanism associated with excessive body weight (Dale et al., 1998). Overweight women also have a suboptimal ovarian response to gonadotrophins in IVF and ICSI cycles. Ovarian responsiveness was studied in 111 patients in an IVF programme; the number of follicles (10 mm obtained after 4 days of stimulation with human menopausal gonadotrophin) and the number of oocytes retrieved were significantly lower in patients in the upper tertiles of BMI (Crosignani et al., 1994). These data have now been confirmed in a larger series of IVF and ICSI patients (Perotti et al., 1999). Moreover, in
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Table 2. Weight loss, pregnancy rate and abortion rate in two groups of overweight patients (modified from Clark et al., 2000). Group A = conventional treatment, group B = support group programme.
Weight loss (kg after 6 months) Pregnancies after 18 months (n (%)) Early pregnancy losses (n (%))
Group A (n = 84)
Group B (n = 87)
1.3
4.7a
18 (21.4)
53 (60.9)b
3 (16.6)
6 (11.3)
aP = 0.001. bSupport group programme: group session programme including diet, exercise and psychological support.
obese PCOS patients there is a higher risk of ovarian hyperstimulation syndrome and multiple pregnancy using conventional gonadotrophin treatment or assisted reproduction techniques (Franks, 1995).
Overweight women: pro-fertility effect of weight reduction Weight reduction can change the picture. Weight loss can improve menstrual cycle rhythm, ovulation, fertility and, in PCOS patients, it can reduce hirsutism, hyperandrogenaemia and insulin resistance. In 1995 and 1998, Clark et al. demonstrated that weight loss is able to re-establish ovulation in obese anovulatory patients or to improve their response to ovulation induction. In a series of 67 anovulatory women, 90% resumed ovulation after weight loss, 78% conceived (33% spontaneously) and 67% achieved a live birth (Clark et al., 1998). These data have now been reconfirmed in a larger number of patients in a study maximizing weight loss through exercise and psychological support (Table 2) (Clark et al., 2000). In another study on obese, non-PCOS patients, weight loss resulted in a significant reduction in blood glucose, insulin, androstenedione, dihydrotestosterone and oestradiol
concentrations (Hollmann et al., 1996). These effects were even more evident in obese PCOS patients (Lefebvre et al., 1997; Pasquali et al., 1997). In these women, weight loss reduces circulating androgens and raises SHBG (Kiddy et al., 1990), enhances insulin sensitivity (Guzick et al., 1994; Andersen et al., 1995; Holte et al., 1995; Huber-Bucholz et al., 1999) and consistently improves menstrual cyclicity and fertility rates (Bates and Whitworth, 1982; Pasquali et al., 1989, Franks et al., 1991). Anthropometric indices in young overweight women while dieting show a critical change of body fat distribution with a lower waist to hip ratio and loss of fat mass (Table 3) (Crosignani et al., 1999). Ovarian morphology also changes, with a significant reduction in volume (Crosignani, unpublished data). In this series, among the 21 out of 26 patients with irregular menstrual cycles who lost weight, 15 re-established regular cycles (71%). Of the 26 patients with anovulation before dietary treatment, 69% of the serum progesterone assessments performed during the diet showed ovulatory values. During a study period of 6 months, eight spontaneous pregnancies were obtained in the 26 patients who lost weight (31% pregnancy rate per patient). Neither menstrual cycle improvement nor ovulatory values of progesterone, and no pregnancies were obtained in the 12 patients who did not lose weight (Crosignani et al., 1999).
Metformin Because of the role of insulin resistance in promoting anovulation in obese patients, insulin sensitizing agents have been employed with the aim of restoring spontaneous ovulation and fertility in obese PCOS patients. Metformin, a biguanide that improves the action of insulin at the cellular level without affecting insulin secretion (Barley et al., 1996), appears very promising. In a study of 22 oligo/amenorrhoeic PCOS patients who underwent a 6-month course with 500 mg metformin three times a day, 21 (95.7%) showed a restoration of menstrual cycles and four (19%) became pregnant. This was accompanied by a reduction in LH and free testosterone serum concentrations (Velazquez et al., 1997). In another study of 61 obese PCOS patients, metformin was compared with placebo: metformin significantly lowered the serum insulin response to oral glucose. Moreover, patients treated with metformin showed marked increases in both spontaneous and clomiphene-induced ovulation (Nestler et al., 1998). In a third
Table 3. Body fat distribution and anthropometric indexes before and during dietary treatment (Crosignani et al., 1999). Basal (26 patients and controls)
5% weight loss (18 patients)
10% weight loss (10 patients)
80.6 ± 0.7
75.0 ± 9.0a
68.9 ± 8.2a
Body mass index (kg/m2) 31.7 ± 4.3
29.5 ± 4.5a
27.1 ± 3.4a 31.7 ± 3.0b 0.83 ± 0.05a
Weight (kg)
62
Arm muscle area
33.3 ± 3.0
32.6 ±
3.0a
Waist–hip ratio
0.89 ± 0.06
0.87 ±
0.06a
Total body water (l)
35.8 ± 2.6
35.8 ± 3.4
Free fat mass (kg)
46.8 ± 3.3
46.5 ± 4.0
45.2 ± 2.5
Fat mass (kg)
33.8 ± 6.9
29.7 ± 7.5a
23.8 ± 6.8a
aP < 0.001; bP < 0.05 versus basal values (t-test for paired data).
34.6 ± 3.3
Reviews - Resumption of fertility in overweight women - PG Crosignani et al.
study of 20 obese PCOS patients, these data were confirmed by a reduction in mean testosterone and leptin concentrations and more regular menstrual cycles during therapy (MorinPapunen et al., 1998a,b). Pasquali et al. (2000) showed that long-term treatment with metformin in obese women is associated with a consistent reduction of abdominal fat and lowered concentrations of serum insulin, testosterone and leptin. These changes were more pronounced in patients with PCOS. Similar endocrine changes associated with a 23% ovulation rate have been recently reported in a large placebo controlled study in anovulatory women with oligomenorrhoea and/or PCOS (Fleming et al., 2002). Interestingly, it appears that metformin can improve hyperinsulinaemia and insulin sensitivity independently of changes in body weight (Glueck et al., 1999; Moghetti et al., 2000). In addition, metformin decreases androgen production in human theca cells (Attia et al., 2001). Nevertheless co-administration of metformin during gonadotrophin treatment in PCOS patients resistant to clomiphene citrate did not improve the clinical outcome in all studies (Stadtmauer et al., 2001; Yarali et al., 2002). Metformin administration during pregnancy to women with PCOS seems to reduce the first-trimester pregnancy loss (Jakubowicz et al., 2002) and the risk of gestational diabetes in hyperinsulinaemic patients (A. Lanzone, personal communication).
Laparoscopic ovarian electrocautery In the last 10 years, laparoscopic ovarian electrocautery (ovarian drilling) has been widely used as a nonpharmacological method of inducing ovulation. The mechanism underlying the electrocautery procedure is not yet known, but it has been shown that after the treatment there is a consistent decrease in peripheral androgen concentrations with a subsequent decline in LH (Aakvaag and Gjonnaess, 1985). These changes are not accompanied by a parallel improvement in insulin sensitivity (Lemieux et al., 1999). Transvaginal ovarian drilling with hydrolaparoscopy appears an interesting alternative to the more invasive laparoscopic approach (Fernandez et al., 2001). Again, the rate of ovulation obtained after this treatment is significantly lower in obese patients (Gjonnaess, 1994; Liguori et al., 1996).
Conclusions Being overweight in itself can cause normogonadotrophic anovulation, interfering in the normal ovulatory mechanism. Considering its prevalence among women of reproductive age, overweight appears to be one of the major and still neglected causes of infertility. Being overweight may also aggravate existing chronic anovulation linked to PCOS. Moreover, overweight patients show high rates of early miscarriage and are less responsive both to ovulation induction and to ovarian stimulation for assisted reproduction techniques. Appropriate counselling to encourage weight loss through dieting and exercise can help restore spontaneous fertility or improve the results of pro-fertility treatments, avoiding frustration and disappointment and saving time and money. Besides helping re-establish fecundity, this strategy is also likely to improve the woman’s overall health. Pharmacological agents to increase insulin sensitivity, although promising, need to be tested in larger controlled studies.
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