Effect of Obesity on Fertility in Women with Polycystic Ovary Syndrome

 

Duvey Brijesh Kumar1, Chand Subash1, Parashar Bharat1, Dharmesh Sharma2, Dhamija Hitesh1

1Department of Pharmacology, Manav Bharti University, Solan

2Department of Pharmacology, Himachal Dental College, Sunder Nagar

*Corresponding Author E-mail: brijesh.duvey@gmail.com

 

ABSTRACT:

Obesity (with body mass index > 30 kg/m2) is an important pathological factor which influences the development of hyperandrogenism in women with polycystic ovary syndrome (PCOS). Obese women, particularly those with central obesity, have more difficulty to conceive per cycle. Obese women suffer with irregular menstrual cycle which affect the body hormonal system. Thus obesity affect ovulation, endometrial growth and nidation There fore weight loss have several beneficial effects upon clinical, endocrinological and metabolic features of obese women presenting with PCOS. In fact, weight loss is associated with a significant improvement in menses abnormalities, ovulation and fertility rates, and with a reduction of hyperandrogenism, hyperinsulinaemia, and altered gonadotrophin pulsatile secretion. The central role of improved insulin concentrations and insulin-resistant state is emphasized by the fact that similar effects can be achieved by both short- and long-term administration of metformin, an insulin lowering drug which ameliorates peripheral insulin action in non-diabetic insulin resistant states. We therefore recommend weight loss as a first-line therapeutic option in all women with obesity and Polycystic ovary syndrome (PCOS). And it may be chive by both pharmacological (drug used to suppress apatite) and non pharmacological (life style modification, diet etc.) treatment.

 

KEYWORDS: Obesity, Polycystic ovary syndrome, infertility, weight loss

 

 


INTRODUCTION:

A number of women with polycystic ovary syndrome (PCOS) are overweight or obese. This association has great deal of interest particularly since the discovery of that PCOS women are often hyperinsulinaemic and that the degree of hyperandrogenism may be positively and significantly correlated with that of hyperinsulinaemia.1,21 The association between obesity and menstrual disorders, hyperandrogenism and polycystic ovaries was firstly described by Stein and Leventhal (1935) and subsequently confirmed by many other authors.4,23 There is a close relationship between the onset of menstrual disorders and overweight, particularly at the time of menarche and during puberty.16,17] Evidence suggests that the onset of obesity in this period of life could play a crucial role in the subsequent development of PCOS.27

 

Although comparisons of the hormonal status between obese and non-obese women with PCOS have yielded conflicting results19 there are numerous studies indicating that obese PCOS women may have more severe hyperandrogenism and lower sex hormone-binding globulin (SHBG) concentrations with respect to their nonobese counterparts. Obese PCOS women have menstrual irregularities and they often present with acanthosis nigricans4,19 Moreover, they are frequently hyperinsulinaemic and insulin resistant, both disorders which can only be partially explained by the degree of overweight and excess body fat.15,16,19

 

PATHOPHYSIOLOGICAL ASPECTS OF THE OBESITY-RELATED HYPERANDROGENISM IN WOMEN WITH PCOS:

Pathophysiology of polycystic ovary syndrome (Pasquali and Casimirri, 1993). Explain both insulin resistance and hyperinsulinaemia in PCOS, regardless of whether they are obese or non-obese. In fact, the pattern of body fat distribution have significantly different effects not only on hormones and metabolism, but also on the clinical features of women with PCOS (Pasquali et al, 1994). We examined a large group of 97 consecutive hyperandrogenic women with PCOS and we divided them into three groups, based on their waist-to-hip ratio values, which can be adequately used to define abdominal against peripheral body fat distribution. Compared with the group with peripheral fat prevalence and after adjusting for body mass index and age, PCOS women with abdominal body fat distribution had higher luteinizing hormone (LH), oestrone and androstenedione concentrations, higher concentrations of both fasting and glucose-stimulated insulin, a greater prevalence of hirsutism, acanthosis nigricans and obesity, and a more atherogenic lipid profile.15 There may be various mechanisms by which obesity may influence hyperandrogenism in pre-menopausal women with PCOS. As we know candidate factors may be oestrogens, insulin and the insulin growth factor system, the opioid system, and diet (Figure 1). It is well known that obesity, particularly the abdomino-visceral (central) phenotype, is associated with supranormal oestrogen production, due to increased activity of the aromatase system.PCOS women with central adiposity have higher oestrone concentrations compared with women with a peripheral fat distribution.19,12 In addition, reduced SHBG values, which usually accompany obesity, privileges greater amounts of free oestradiol to be delivered to target tissues, including fat tissue. Obese women are also characterized by reduced formation of inactivated oestrogen metabolites (i.e. oestradiol metabolites hydroxylated in the C2 position and oxidized at the 17 position), and by greater availability of oestrone suphate in the target tissues. All these conditions concur in privileging a hyper-estrogenic state in obese women. Since oestrogens exert a positive feed-back regulation upon gonadotrophin release,27 Pathophysiology of polycystic ovary syndrome.15 Explain both insulin resistance and hyperinsulinaemia in PCOS, regardless of whether they are obese or non-obese. In fact, the pattern of body fat distribution have significantly different effects not only on hormones and metabolism, but also on the clinical features of women with PCOS.19 We examined a large group of 97 consecutive hyperandrogenic women with PCOS and we divided them into three groups, based on their waist-to-hip ratio values, which can be adequately used to define abdominal against peripheral body fat distribution. Compared with the group with peripheral fat prevalence and after adjusting for body mass index and age, PCOS women with abdominal body fat distribution had higher luteinizing hormone (LH), oestrone and androstenedione concentrations, higher concentrations of both fasting and glucose-stimulated insulin, a greater prevalence of hirsutism, acanthosis nigricans and obesity, and a more atherogenic lipid profile.19

 

Beneficial Effect of Weight Loss on Clinical Features, Hormones and Metabolism In Women With Obesity And Pcos:

Initially the effects of weight loss of women with obesity and PCOS have been neglected, whereas impressive clinical attempts have been made in the pharmacological management of the syndrome. However, there is long-standing clinical evidence occupying the efficacy of weight reduction upon both clinical and endocrinological features of obese women presenting with PCOS (Table I).

 

Table I. Effects of weight loss on hormones, metabolism, and clinical features in obese women with polycystic ovary syndrome

Effect

Parameters

Reduced

Total and visceral body fat

Improved

 

Hirsutism score Menstrual cycles (no.) Fertility ratea

Acanthosis nigricans

Reduced

Testosterone

 

Androstenedione

 

Insulin

Improved

Insulin sensitivity

Unchanged/increased

Sex hormone binding globulin

Unchanged/reduced

Luteinizing hormone

 

 

Weight loss may improve menstruation abnormalities and, most importantly, both ovulation and fertility rate.[18] Moreover, in two separate studies we found that hirsutism significantly improved in most of the patients, as did acanthosis nigricans.17,18 Reduction of hyperandrogenaemia seems to be the key factor responsible for these effects. In fact, peripheral testosterone, androstenedione and dehydroepiandrosterone sulphate values were significantly reduced after weight loss in obese PCOS women. These findings were subsequently confirmed by Kiddy et al. (1990)10 in women who had obtained even only moderate weight loss (>5 kg) after long-term low calorie regimen. Furthermore, it is found that weight loss was associated with a significant increase of SHBG and a reduction of the free-testosterone values. There is no significant benefit was observed in women who lost <5 kg, maintained their excess body weight or increased it. While weight loss may decrease LH pulse amplitude.8 which, successively, can be followed by reduced androgen production. An important beneficial effect of weight reduction is the reduction of the degree of hyperinsulinaemia. This fact obviously improves the insulin resistant state. Changes in testosterone and insulin (both basal and glucose-stimulated) concentrations may be significantly correlated, regardless of body weight variations.10,18 Recent studies have suggested that hyperinsulinaemia may be responsible for increased activity of the ovarian cytocrome P450cl7 system, which has been indicated as playing a key role in determining ovarian hyperandrogenism in many PCOS women.2 Reduction of insulin concentrations by metformin13 and diet has been demonstrated to reduce this enzyme activity and, consequently, ovarian androgen production. Recently we found that obese PCOS women undergoing hypocaloric dietary treatment coupled with antiandrogen (cyproterone acetate plus ethynilestradiol) or metabolic drugs (such as metformin or dexfenfluramine) had a similar degree of weight loss and also a similar decrease testosterone serum concentrations (unpublished data).

 


 

Figure - Flow chart of hormonal, metabolic and nutritional factors showing Pathophysiology of PCOS

 

 


Therefore, bettering peripheral sensitivity by both diet and drugs may be as effective as diet and antiandrogen therapy in reducing the degree of hyperandrogenism in women with obesity and PCOS. To summarize, the principal effects of weight loss on both clinical and endocrinological features in women with obesity and PCOS include not only the reduction of total and particularly visceral fat, but also improve menstrual cycles and fertility rate, reduce androgen and insulin concentrations, and improve insulin sensitivity. The effects of dietary-induced weight loss on androgens seem to be special to obese hyperandrogenic women, since they have not been reported in non-PCOS obese women.6

 

CONCLUSIONS AND PERSPECTIVES:

In brief we may summaries that obesity is a pathogenetic factor in susceptible individuals in developing hyperandrogenism and PCOS and is related to hormonal and metabolic abnormalities of women with obesity and PCOS. Future research will be directed towards:

(i)       characterization of PCOS women in whom obesity may play a key role in determining the syndrome, with their genetic background;

(ii)     The role of different diet to manage these patients, particularly with insulin-lowering regimens;

(iii)    defining the role of new antiandrogenic drugs, such as flutamide and finasteride, and that of metabolic drugs, such as metformin, dexfenfluramine and troglitazone.

At present, we believe that any treatment of women with obesity and PCOS should firstly include a 3-6 month low-calorie diet schedule in order to obtain weight loss and related benefit with regard to both clinical and endocrinological features of the patients. This therapeutic schedule might be applied even in conjunction with other pharmacological procedures aimed at achieving pregnancies, since weight loss has been demonstrated to favour ovulation and improve fertility in obese women with PCOS.

 

ACKNOWLEDGEMENT:

I avail this opportunity, with great pleasure and deep sense of gratitude, to express my thanks to my reverent guide Dr. Bharat Parashar and Mr. Dharmesh Sharma. I am profoundly indebted for his constant inspiration, valuable suggestions, guidance and excellent facilities, with which he led to me to the successful completion of this work. I am extremely thankful to my parent, for there numerous ideas, guidance and constant encouragement. I pay my grateful thanks to Mrs. Deva Sharma and Mrs. Madhu Shaklani, librarian Manav Bharti University, Solan, for their continuous support in writing this article. My sincere thanks to Mr. Subash Chand for helping me.

 

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Received on 05.11.2011 Accepted on 01.12.2011

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Asian J. Res. Pharm. Sci. 1(4): Oct.-Dec. 2011; Page 127-130