Effects of metformin on adrenal steroidogenesis in women with polycystic ovary syndrome

Marca, Antonio La; Morgante, Giuseppe; Paglia, Tiziana; Ciotta, L; Cianci, Antonio; Leo, Vincenzo De

doi:10.1016/s0015-0282(99)00407-0

Cited by 97 publications

(42 citation statements)

References 16 publications

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“…It contradicts a study (11) which found a decrease in its activity after metformin treatment. Unfortunately, it was not possible to examine the activity of C17,20 hydroxylase in both (D4 and D5) pathways.…”

Section: ) Although Not With Those Obtained By Others (12± 15)contrasting

confidence: 82%

“…After 1 month of metformin treatment, la Marca et al (11) found a significant reduction in the maximum increment and area under the curve of 17OHP, androstenedione, testosterone and free testosterone after ACTH stimulation, and decreases in the 17OHP/progesterone ratio (an index of C17 hydroxylase activity) and androstenedione/17OHP ratio (an index of the activity of C17,20 lyase in the D4 pathway). On the other hand, Unluhizarci et al (10) found no difference in 17OHP or androstenedione response after ACTH stimulation, after a 3-month course of metformin.…”

Section: ) Although Not With Those Obtained By Others (12± 15)mentioning

confidence: 99%

“…It has multiple mechanisms of action, including the inhibition of gluconeogenesis in the liver, and the stimulation of peripheral glucose uptake (8); interestingly, there is also some evidence for the direct inhibitory effect of metformin on ovarian steroidogenesis (9). The literature to date contains only few data about the effects of metformin on adrenal steroidogenesis in women with PCOS (10,11).…”

Section: Introductionmentioning

confidence: 99%

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The effects of long-term metformin treatment on adrenal and ovarian steroidogenesis in women with polycystic ovary syndrome

et al. 2001

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Objective: To evaluate adrenal and ovarian steroidogenesis before and after long-term treatment with metformin in women with polycystic ovary syndrome (PCOS). Design and Methods: Twenty-four women with PCOS were evaluated before and after treatment (27^4 weeks) with metformin (1000 mg/day) using adrenocorticotrophin (ACTH), GnRH analogue and oral glucose tolerance (oGTT) tests. For statistical evaluation, ANOVA and Wilcoxon's test were used. Results: In 58% of the women a significant improvement in menstrual cyclicity was observed. No significant change in basal steroid levels was found. After ACTH stimulation, a significant decrease in the activity of 3b-hydroxysteroid dehydrogenase in C 21 steroids P , 0X05 and in 17b-hydroxysteroid dehydrogenase P , 0X01 was observed, as was an increase in the activity of C17,20-lyase in the D 4 pathway P , 0X01X A significant growth in the dehydroepiandrosterone (DHEA)/DHEA-sulfate ratio P , 0X05 was detected. With regard to ovarian steroidogenesis, a significant decrease in the stimulated levels of testosterone P , 0X05Y index of free testosterone P , 0X01Y LH P , 0X05 and oestradiol P , 0X01Y and an increase in the levels of 17-hydroxypregnenolone P , 0X05 were detected. In the indices of ovarian enzyme activities, we observed a significant decrease in 3b-hydroxysteroid dehydrogenase in C 21 steroids P , 0X01Y in C17,20-lyase in the D5 pathway P , 0X01Y in 17b-hydroxysteroid dehydrogenase P , 0X05 and in aromatase. In glucose metabolism, a tendency towards reduction in the homeostasis model assessment (HOMA)-R (for insulin resistance) and HOMA-F (for b cell function) was detected. In addition, an increase in the levels of C peptide during oGTT was observed P , 0X01X Conclusions: Long-term metformin treatment reduced various steroid enzymatic activities both in the ovary and the adrenal glands, without apparent changes in basal steroid levels and in insulin sensitivity.

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Section: ) Although Not With Those Obtained By Others (12± 15)contrasting

confidence: 82%

Section: ) Although Not With Those Obtained By Others (12± 15)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The effects of long-term metformin treatment on adrenal and ovarian steroidogenesis in women with polycystic ovary syndrome

et al. 2001

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“…A number of studies have found (19,20). The mechanisms for the adrenal hyperandrogenism remain unclear and several hypotheses have been put forward to explain the association between PCOS and adrenal hyperandrogenism: enhanced ovarian and adrenal P450c17a enzyme activity (21), increased activity of enzymes involved in cortisol clearance such as 11b-hydroxysteroid dehydrogenase (22) and the possible role of hyperinsulinemia (5,23). Additionally, the role of the ovary in adrenal androgen hypersecretion is a matter of debate.…”

Section: Discussionmentioning

confidence: 99%

A comparison between the effects of low dose (1 microg) and standard dose (250 microg) ACTH stimulation tests on adrenal P450c17alpha enzyme activity in women with polycystic ovary syndrome

Çolak

Keleştimur

Ünlühızarcı³

et al. 2002

European Journal of Endocrinology

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A comparison between the effects of low dose (1 mg) and standard dose (250 mg) ACTH stimulation tests on adrenal P450c17a enzyme activity in women with polycystic ovary syndrome AbstractObjective: Numerous studies have found elevated androgen production by the adrenal glands in patients with polycystic ovary syndrome (PCOS). However, the role and the mechanisms responsible for the adrenal androgen excess in women with PCOS are not well understood. Design: Our aim was to compare 17-hydroxyprogesterone (17-OHP), androstenedione, dehydroepiandrosterone sulfate (DHEAS) and cortisol responses to a low dose (1 mg) ACTH stimulation test (LDT) with the responses to a standard dose (250 mg) ACTH stimulation test (SDT) in patients with PCOS.Methods: Fifty women with PCOS (mean age 25:4^0:7 years) and 20 healthy women (mean age 27:3^2:2 years) were included in the study. The patients and controls underwent ACTH stimulation tests with 1 mg and 250 mg synthetic ACTH in the follicular phase of their cycles. Venous blood was drawn at 0, 30 and 60 min for determination of serum cortisol, 17-OHP, androstenedione and DHEAS levels.Results: In PCOS subjects, peak and area under the curve (AUC) 17-OHP ð9:3^0:3 nmol=l; 378:46 1 nmol=l £ 60 minÞ; androstenedione ð15:6^0:6 nmol=l; 806:4^52 nmol=l £ 60 minÞ and DHEAS ð7:5^0:4 mmol=l; 385:6^25:5 mmol=l £ 60 minÞ responses to SDT were significantly higher than the levels in healthy women (respectively 5:7^0:3 nmol=l and 249:4^52:2 nmol=l £ 60 min for 17-OHP; 9:1^0:3 nmol=l and 413:7^31:6 nmol=l £ 60 min for androstenedione; 4:3^0:4 mmol=l and 224:9^24:5 mmol=l £ 60 min for DHEAS) ðP , 0:05Þ: Peak and AUC cortisol responses to SDT were similar in PCOS and control subjects. Peak and AUC cortisol and 17-OHP responses to LDT in women with PCOS were similar to the values obtained in healthy women. Peak androstenedione ð12:5^0:6 nmol=lÞ and peak ð6:5^0:5 nmol=lÞ and AUC ð336:3^22:4 mmol=l £ 60 minÞ DHEAS responses to LDT were significantly higher in women with PCOS. Conclusions: These results show that LDT is capable of revealing the adrenal hyperactivity in women with PCOS. Adrenal P450c17a enzyme dysregulation in PCOS is revealed by ACTH stimulation at a pharmacological dose (250 mg) but not by a physiological dose (1 mg). LDT is able to demonstrate adrenal hyperactivity characterized by an increase in DHEAS levels.

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“…50,51 In these patients, metformin/ clomiphene combination induces ovulation in 62.5-77.7% of cases. [52][53][54][55][56] Several mechanisms contribute to the induction of ovulation when metformin is combined with clomiphene in clomiphene-resistant anovulatory patients with PCOS: a) changes in intrafollicular steroidogenesis resulting from the effect of metformin on granulosa cells through an increase in insulin-like growth factor 1, 53 b) inhibition of androgen synthesis by the direct action of metformin on the interna thecal cells, 57 c) metformin-induced decrease in adrenal responsiveness to adrenocorticotropic hormone resulting in reduced adrenal steroidogenesis, 58 and d) reduction in serum LH and prolactin levels resulting from the effects of metformin on the hypothalamuspituitary axis. 59 The conventional method of ovulation induction in clomiphene-resistant patients with PCOS was administration of low doses of gonadotropins (starting daily dose of 37.5-75 IU and dose increase after 7 days if there was no follicle >10 mm).…”

mentioning

confidence: 99%

The guidelines issued by the European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine regarding the induction of ovulation with metformin in patients with the polycystic ovary syndrome potentially require reconsideration

Panidis¹,

Τζιόμαλος²,

Papadakis³

et al. 2013

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In 2007, the European Society for Human Reproduction and Embryology (ESHRE) and the American society for reproductive Medicine (AsrM) issued guidelines in Thessaloniki regarding the use of metformin and clomiphene for the induction of ovulation in patients with anovulatory polycystic ovary syndrome (PcOs). According to these guidelines, the use of metformin should be limited to patients with impaired glucose tolerance and should be interrupted well before the administration of clomiphene, thus restricting the use of metformin to a minority of patients with PcOs. More recent data suggest that these guidelines potentially require reconsideration. Indeed, metformin appears to be useful in patients with PCOS who have a body mass index within the normal range and present with infertility due to anovulation. Moreover, the combination of metformin with clomiphene appears to be the best treatment choice in patients with PcOs who are resistant to clomiphene, i.e. it should precede the administration of gonadotropins. In addition, the administration of metformin reduces the incidence and severity of ovarian hyperstimulation syndrome when given to patients with PcOs who undergo multiple ovulation induction for in vitro fertilization and have a high risk for this syndrome. However, it should be emphasized that more studies are needed to support the above arguments and, more importantly, to determine the factors that predict the success of ovulation induction.

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Effects of metformin on adrenal steroidogenesis in women with polycystic ovary syndrome

Cited by 97 publications

References 16 publications

The effects of long-term metformin treatment on adrenal and ovarian steroidogenesis in women with polycystic ovary syndrome

The effects of long-term metformin treatment on adrenal and ovarian steroidogenesis in women with polycystic ovary syndrome

A comparison between the effects of low dose (1 microg) and standard dose (250 microg) ACTH stimulation tests on adrenal P450c17alpha enzyme activity in women with polycystic ovary syndrome

The guidelines issued by the European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine regarding the induction of ovulation with metformin in patients with the polycystic ovary syndrome potentially require reconsideration

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