Metformin treatment of PCOS during adolescence and the reproductive period

doi:10.1016/j.ejogrb.2004.09.015

European Journal of Obstetrics & Gynecology and Reproductive Biology

Volume 121, Issue 1, 1 July 2005, Pages 3-7

https://doi.org/10.1016/j.ejogrb.2004.09.015 Get rights and content

Abstract

Insulin resistance is a common feature of PCOS. Hyperinsulinemia has been causally linked with all features of the syndrome, such as hyperandrogenism, reproductive disorders, and metabolic disturbances. Several insulin-sensitizing agents have been tested in the management of PCOS. Metformin is the only drug currently in widespread clinical use for PCOS. In a high percentage of patients, treatment with metformin is followed by regularization of the menstrual cycle, less pronounced hyperandrogenism and cardiovascular risk factors, and some improvement in the response to therapies aimed at induction of ovulation.

In adolescent girls who are anovulatory and moderately obese, metformin administration can have a normalizing effect on multiple aberrations within the endocrine-metabolic status. During the reproductive period, metformin administration can improve reproductive function and the establishment of pregnancy. A role of metformin in prevention of gestational diabetes and hypertensive complications of pregnancy has yet to be shown. Finally, any real benefit of insulin-lowering treatment in terms of lesser cardiovascular risk in women with PCOS women remains to be demonstrated.

Introduction

Since 1994, the use of metformin in the management of polycystic ovary syndrome (PCOS) has extended our knowledge of the pathophysiology of PCOS [1]. A role of insulin resistance had been suggested in the complex pathophysiology of the syndrome, and researchers investigated this subject by raising (by means of exogenous insulin infusion) or lowering (by administering insulin-sensitizing agents) insulin levels in plasma. Studies involving insulin infusion yielded discordant results, whereas the results of studies based on lowering insulin levels were more nearly homogeneous and confirmed a direct effect of hyperinsulinemia in stimulating the synthesis of adrenal and ovarian androgens and pituitary gonadotropin secretion.

Several insulin-sensitizing agents and insulin-lowering drugs have been used to treat women with PCOS. Some (biguanides, thiazolinediones) will soon form the basis of medical therapy of PCOS; others (diazoxide, somatostatin analogue) have no role except in research.

Section snippets

Treatment during adolescence

Metformin treatment may be an effective new therapeutic tool in girls and women with PCOS, both during adolescence and during the reproductive period. After menarche, adolescent girls have anovulatory menstrual periods for a while. This period is considered physiological within the ontogeny of fertility [2], [3]. However, there is a subgroup of young women in whom regular menstrual cycles fail to occur within 2–3 years after menarche and the anovulatory condition persists.

The literature on

Treatment during the reproductive period

In obese PCOS women of reproductive age, weight reduction is a relevant treatment strategy; however, not all women will achieve the ‘therapeutic’ weight reduction of 6–8%. Furthermore, not all women with PCOS are obese. In the nonobese group of women with PCOS, pharmacological reduction of insulin levels offers an additional therapeutic modality. (The relationship between PCOS-related infertility, hyperinsulinemia and treatment has been extensively reviewed [9], [10].) Interestingly, women who

Treatment during pregnancy

Metformin treatment has been associated with increased glycodelin plasma levels and a reduced resistance index of the uterine spiral arteries, which are thought to be favorable to embryonic implantation and the maintenance of pregnancy [23]. Indeed, preliminary data demonstrate that continuing metformin administration during the first trimester of pregnancy leads to a reduced incidence of spontaneous abortion [24].

Insulin resistance can be considered a risk factor for the development of

Conclusions

In conclusion, metformin may be beneficial in the management of PCOS during adolescence and the reproductive period, but many issues still require elucidation [30]. About half of all women treated with metformin do not respond. This is probably due to the heterogeneity of the syndrome's pathogenesis. Only patients in whom hyperinsulinemia has a major role in the pathogenesis can benefit from therapy based on insulin-sensitizing agents. Insulin resistance is not easily recognized. Techniques are

Condensation

Metformin may be beneficial in the management of PCOS during adolescence and the reproductive period.

References (33)

E.M. Velazquez et al.
Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy
Metabolism
(1994)
L. Ibáñez et al.
Insulin sensitization early after menarche prevents progression from precocious pubarche to polycystic ovary syndrome
J Pediatr
(2004)
M.O. Goodarzi et al.
The importance of insulin resistance in polycystic ovary syndrome
Fertil Steril
(2003)
I. Pirwany et al.
Laparoscopic treatment of polycystic ovaries: is it time to relinquish the procedure
Fertil Steril
(2003)
E.S. Sills et al.
Correction of hyperinsulinemia in oligoovulatory women with clomiphene-resistant polycystic ovary syndrome: a review of therapeutic rationale and reproductive outcomes
Eur J Obstet Gynecol Reprod Biol
(2000)
V. De Leo et al.
Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome
Fertil Steril
(1999)
L.A. Stadtmauer et al.
Metformin treatment of patients with polycystic ovary syndrome undergoing in vitro fertilization improves outcomes and is associated with modulation of the insulin-like growth factors
Fertile Steril
(2001)
O. Acbay et al.
Can metformin reduce insulin resistance in polycystic ovary syndrome?
Fertil Steril
(1996)
S.H. Belli et al.
Effect of rosiglitazone on insulin resistance, growth factors, and reproductive disturbances in women with polycystic ovary syndrome
Fertil Steril
(2004)
G. Ghazeeri et al.
Effect of rosiglitazone on spontaneous and clomiphene citrate-induced ovulation in women with polycystic ovary syndrome
Fertil Steril
(2003)

M.F. Costello et al.

A systematic review of the reproductive system effects of metformin in patients with polycystic ovary syndrome

Fertil Steril

(2003)

M.A. Bedaiwy et al.

Effect of metformin on mouse embryo development

Fertil Steril

(2001)

C.J. Glueck et al.

Polycystic ovary syndrome, infertility, familial thrombophilia, familial hypofibrinolysis, recurrent loss of in vitro fertilized embryos, and miscarriage

Fertil Steril

(2000)

M.J. de Vries et al.

Higher risk of preeclampsia in the polycystic ovary syndrome. A case control study

Eur J Obstet Gynecol Reprod Biol

(1998)

P.A. Radon et al.

Impaired glucose tolerance in pregnant women with polycystic ovary syndrome

Obstet Gynecol

(1999)

C.J. Glueck et al.

Metformin to restore normal menses in oligo-amenorrheic teenage girls with polycystic ovary syndrome (PCOS)

J Adolesc Health

(2001)

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Although physiological hyperandrogenism can be observed during puberty and at the menarche,13 the presence of hirsutism may be extremely distressing for young patients and may have profound negative impact on their psychosocial development for at least 2 reasons: a cosmetic reason, since excessive body, and particularly facial, hair in women is considered unattractive in Western societies; and an endocrine reason, as hirsutism may be the outcome of increased ovarian or adrenal androgen production.14 There are little data on intervention in the adolescent population with hirsutism.15,16 The therapeutic options of hirsutism can be divided into systemic, topical, and dermocosmetic therapies.
Hirsutism has negative impact on adolescent psychosocial development for both cosmetic and endocrine reasons. This study evaluated the effectiveness of a new intermittent, low-dose finasteride regimen consisting of 2.5 mg of drug given every 3 days (1 day of treatment, 2 days of drug withdrawal) for 6 months in girls with hirsutism by polycystic ovarian syndrome (PCOS) or idiopathic hirsutism (IH).
Twenty-eight girls (15-19 y old) with hirsutism were randomly assigned to 2 treatment groups and treated for 6 months. Fourteen patients (7 with IH, 7 with PCOS) received finasteride; fourteen patients (7 with IH, 7 with PCOS) received placebo. Hirsutism score (HS), clinical, and hormonal effects were compared between the 2 groups.
In patients treated with finasteride, the HS value at 6 months was 52.9% lower than that observed at baseline in girls with IH, and 52.8% lower in girls with PCOS (P < .0001 for both). Similarly, the 3α-17 β-androstenediol glucuronide serum levels were decreased by 34.8% in patients with IH, and by 47.5% in patients with PCOS (P < .0001, respectively). Finasteride treatment was well tolerated and did not alter values of BMI, serum levels of sexual hormones, metabolic parameters related to liver and kidney function as well as glycemic and lipidic asset.
A low-dose of finasteride, given every 3 days, reduces the HS in young patients affected by PCOS or IH. Compared with conventional continuous finasteride administration, the intermittent low-dose regimen has similar efficacy with the advantage to be safer and less expensive.
Polycystic ovary syndrome: Challenges in adolescence
2010, Endocrinologia y Nutricion
Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases in women of reproductive age. PCOS typically develops during adolescence and is a heterogeneous syndrome classically characterized by features of anovulation combined with signs of androgen excess (hirsutism, acne). Increasing obesity in adolescents probably exacerbates signs of PCOS, contributing to its earlier recognition. Recognizing the features of this syndrome can be very challenging in adolescence. Although adolescents’ concerns are often cosmetic, if left untreated these girls are at risk for diabetes, metabolic syndrome, and infertility as they mature. Efforts should be made to diagnose and treat PCOS to minimize the development of symptoms and prevent the onset of cardiovascular and metabolic disturbances.
El síndrome del ovario poliquístico (SOP) es una de las endocrinopatías más comunes en mujeres en edad reproductiva. SOP se presenta típicamente en la adolescencia y es un síndrome heterogéneo que clásicamente se caracteriza por rasgos de la anovulación en combinación con síntomas de exceso de andrógenos (hirsutismo, acné). El aumento de la obesidad en los adolescentes probablemente exacerba señales del SOP, contribuyendo a un reconocimiento más precoz. Reconocer las características de este síndrome puede ser muy difícil en la adolescencia. Aunque las preocupaciones a los adolescentes sean a menudo cosméticas, si no se tratan estas niñas corren el riesgo de desarrollar diabetes, síndrome metabólico, e infertilidad a medida que crecen. Se deben hacer esfuerzos para diagnosticar y tratar el SOP a fin de minimizar el desarrollo de los síntomas y prevenir la aparición de problemas cardiovasculares y metabólicos.
Polycystic ovary syndrome in perimenarchal obese adolescents: experience with magnetic resonance imaging
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The aim of the study was to assess the diagnostic accuracy of pelvic ultrasound (PUS) and magnetic resonance imaging (PMRI) in detecting polycystic ovary syndrome (PCOS) in hyperandrogenic obese adolescent females with menarche age under 2 years compared with healthy females of the same age.
We studied 10 patients of mean age 14.63±1.26 years (±SD range: 12.3–16.2 years), of gynaecological age under 2 years, with clinical and biochemical hyperandrogenism. Other causes of hyperandrogenism were excluded. Out of 10 patients, seven had PUS suggestive of PCOS and three were doubtful. All patients had a body mass index over 95th centile and all underwent PUS and PMRI in early follicular phase (1st to 7th day of cycle). Nine healthy, non-obese girls of the same age formed the control group.
Using PUS in the 10 patients with suspicion of PCOS, ovary volume was found to be <10 ml in seven and doubtful in three. In nine patients, less than 12 follicles were found. Using PMRI, ovary volume was >10 ml in all the patients except one in whom the volume was <10 ml; all the subjects had more than 12 follicles in the ovaries. In the control group (n = 9), the ovary volume was <10 ml using PUS and PMRI in all subjects but one who had a 10 ml volume. All the control subjects showed <12 follicles with either PUS or PMRI.
In adolescent girls with suspected PCOS, especially if obese, PMRI is a useful and accurate method for analysing ovary volume or structure alterations. Our data showed that PMRI may be a valid alternative for precocious diagnosis of PCOS in adolescents when PUS is negative or doubtful.
Polycystic Ovary Syndrome in Adolescents
2008, Journal of Pediatric and Adolescent Gynecology
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The thazolinediones, troglitazone, rosiglitazone, and pioglitazone also improve ovulation and reduce androgens in adult women; however, troglitazone was associated with hepatotoxicity and the newer drugs need further studies in adolescents.1 Metformin has been studied in several small series of adolescent girls with PCOS55 as summarized in Table 3. In general, metformin appears to improve insulin levels, reduce androgens, and lead to more regular menstrual cycles.
Effects of lifestyle modification in polycystic ovarian syndrome
2006, Reproductive BioMedicine Online
Polycystic ovarian syndrome (PCOS) is a common endocrine condition with reproductive and metabolic consequences, including anovulation, infertility and an increased prevalence of diabetes mellitus. Obesity, central obesity and insulin resistance are strongly implicated in its aetiology. Dietary weight loss is recommended as the primary treatment strategy; however, effective means of achieving and maintaining weight loss and reproductive and metabolic improvements are unknown. Lifestyle modification programmes with an emphasis on behavioural management and dietary and exercise interventions have been successful in the general population in reducing the risk of diabetes and the metabolic syndrome, and have had some initial success in improving fertility outcomes in PCOS. However, the literature on effective diet and exercise programmes for PCOS has been sparse, and structured advice for implementing components of lifestyle modification programmes should be assessed in this population.
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ReviewMetformin treatment of PCOS during adolescence and the reproductive period

Abstract

Introduction

Section snippets

Treatment during adolescence

Treatment during the reproductive period

Treatment during pregnancy

Conclusions

Condensation

Metabolism

J Pediatr

Fertil Steril

Fertil Steril

Eur J Obstet Gynecol Reprod Biol

Fertil Steril

Fertile Steril

Fertil Steril

Fertil Steril

Fertil Steril

Fertil Steril

Fertil Steril

Fertil Steril

Eur J Obstet Gynecol Reprod Biol

Obstet Gynecol

J Adolesc Health

Review
Metformin treatment of PCOS during adolescence and the reproductive period