Metformin directly inhibits androgen production in human thecal cells

G R Attia; W E Rainey; B R Carr

doi:10.1016/s0015-0282(01)01975-6

Fertility and Sterility, 76(3), 517-524, 2001

Metformin directly inhibits androgen production in human thecal cells

Attia GR, Rainey WE, Carr BR

Author affiliations (2)

The University of Texas Southwestern Medical Center ROR
Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-9032, USA.

DOI10.1016/s0015-0282(01)01975-6 PMID11532475

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Abstract

Objective

To examine the direct effect of metformin on thecal cell androgen production.

Setting

Basic science research laboratory, University of Texas Southwestern, Dallas, Texas.

INTERVENTION(S): Human ovarian theca-like tumor cells were treated with various concentrations of metformin in the presence and absence of forskolin for 48 hours.

MAIN OUTCOME MEASURE(S): Media were collected, and radioimmunoassay (RIA) for progesterone, 17 alpha-hydroxyprogesterone (17OHP), androstenedione, and testosterone was performed. The effect of metformin on the expression of various enzymes involved in theca cell steroidogenesis was examined.

RESULT(S): Metformin (50 microM and 200 microM) significantly inhibited androstenedione production from both forskolin-stimulated and unstimulated theca cells. Testosterone production was also significantly inhibited in forskolin-treated cells in the presence of 200 microM of metformin-treated compared with forskolin-only-treated cells. Western blot analysis revealed that metformin significantly inhibited the expression of steroidogenic acute regulatory (StAR) protein and 17 alpha-hydroxylase (CYP17) expression in cells stimulated with forskolin compared with forskolin treatment alone. There was no significant change in either 3beta-hydroxysteroid dehydrogenase (3 beta HSD) or cholesterol side-chain cleavage (CYP11A1) protein expression. Northern analysis revealed a significant decrease in the expression of CYP17 mRNA in forskolin-stimulated cells treated with metformin (200 microM) compared with forskolin-only-treated cells, however, there was no significant change in steroidogenic acute regulatory protein mRNA expression.

CONCLUSION(S): Our results suggest that metformin may have a direct effect on thecal cells' androgen production.

Topics

Reproductive Endocrinology: Ovarian Hormones Androgens
Therapeutics: Metabolic and Endocrine Agents Insulin Sensitizing Agents

metformin direct inhibition androgen production thecal cells, metformin StAR protein CYP17 expression ovarian theca, PCOS metformin mechanism androstenedione testosterone reduction, human theca cell steroidogenesis metformin in vitro, metformin 17 alpha hydroxylase inhibition androgen synthesis, Attia Carr metformin thecal cell androgen production, forskolin stimulated theca cell metformin steroidogenic enzymes, polycystic ovary syndrome metformin ovarian androgen mechanism, metformin steroidogenic acute regulatory protein expression, in vitro metformin effect ovarian steroid biosynthesis

PMID 11532475 11532475 DOI 10.1016/s0015-0282(01)01975-6 10.1016/s0015-0282(01)01975-6 Attia et al. 2001, Attia 2001

Cite this article

Attia, G. R., Rainey, W. E., & Carr, B. R. (2001). Metformin directly inhibits androgen production in human thecal cells. Fertility and sterility, 76(3), 517-524. https://doi.org/10.1016/s0015-0282(01)01975-6

Keywords

17-alpha-Hydroxyprogesterone/metabolism, 3-Hydroxysteroid Dehydrogenases/genetics, Androgens/biosynthesis, Androstenedione/metabolism, Cells, Cultured, Cholesterol Side-Chain Cleavage Enzyme/genetics, Colforsin/pharmacology, Female, Gene Expression Regulation, Enzymologic/drug Effects, Humans, Metformin/pharmacology, Phosphoproteins/genetics, Progesterone/metabolism, RNA, Messenger/genetics, Steroid 17-alpha-Hydroxylase/genetics, Testosterone/metabolism, Theca Cells/cytology/drug Effects/metabolism, Transcription, Genetic/drug Effects, Androgens, Phosphoproteins, RNA, Messenger, Steroidogenic Acute Regulatory Protein, Colforsin, Testosterone, Androstenedione, Progesterone, 17-alpha-Hydroxyprogesterone, Metformin, 3-Hydroxysteroid Dehydrogenases, Steroid 17-alpha-Hydroxylase, Cholesterol Side-Chain Cleavage Enzyme

Ovarian Hormones · Androgens

Metformin has direct effects on human ovarian steroidogenesis

Mansfield R et al., 2003 Fertil Steril

To investigate the possibility of direct effects of metformin on ovarian steroidogenesis. Cultured ovarian cells. Academic research environment. PATIENT(S): Women undergoing bilateral salpingoophorectomy for benign gynecological disease. MAIN OUTCOME MEASURE(S): Estradiol and P were measured in granulosa cell (GC) conditioned medium and androstenedione (A) and P in theca conditioned medium. RESULT(S): The effect of addition of metformin alone to GCs was variable, but significant inhibition of both P and E2 was seen (range 0%-30%). Metformin dose-dependently inhibited gonadotrophin and insulin-stimulated P and E2 production (range 25%-50%). In theca, metformin inhibited A production (0%-40%) with no effect on P. In the presence of insulin, A was inhibited dose-dependently and P increased by a similar magnitude. CONCLUSION(S): These results demonstrate a direct effect of metformin on ovarian steroidogenesis. The inhibitory effects on androgen production in particular would be beneficial in polycystic ovary syndrome (PCOS).

Ovarian Hormones · Androgens

Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome

Morin-Papunen LC et al., 1998 Fertil Steril

To determine the clinical, hormonal, and biochemical effects of 4-6 months of metformin therapy in obese patients with polycystic ovary syndrome (PCOS). Prospective study. The Gynecological Endocrine Unit of University Central Hospital, Oulu, Finland. PATIENT(S): Twenty obese patients with PCOS. INTERVENTION(S): Patients were treated with 0.5 g of metformin three times daily for 4-6 months. MAIN OUTCOME MEASURE(S): Clinical symptoms, menstrual pattern, and hirsutism, as well as serum concentrations of sex steroids, sex hormone-binding globulin (SHBG), gonadotropins, and lipids were assessed during the treatment. RESULT(S): Eleven women (68.8% of the women with menstrual disturbances) experienced more regular cycles during therapy. No changes in hirsutism, body mass index, or blood pressure occurred. The mean testosterone level was decreased significantly after 2 months of treatment but returned to the starting level by 4-6 months. Free testosterone levels decreased significantly during the treatment. There was no significant change in the levels of other sex steroids or lipids measured at 4-6 months of treatment. CONCLUSION(S): Metformin therapy is well tolerated by the majority of patients and may be clinically useful, especially in obese patients with PCOS and menstrual disturbances.

Pathophysiology · Insulin Resistance

Polycystic Ovary Syndrome: Etiology, Current Management, and Future Therapeutics

Singh S et al., 2023 Journal of clinical medicine

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder, typically characterized by anovulation, infertility, obesity, insulin resistance, and polycystic ovaries. Lifestyle or diet, environmental pollutants, genetics, gut dysbiosis, neuroendocrine alterations, and obesity are among the risk factors that predispose females to PCOS. These factors might contribute to upsurging metabolic syndrome by causing hyperinsulinemia, oxidative stress, hyperandrogenism, impaired folliculogenesis, and irregular menstrual cycles. Dysbiosis of gut microbiota may play a pathogenic role in the development of PCOS. The restoration of gut microbiota by probiotics, prebiotics, or a fecal microbiota transplant (FMT) might serve as an innovative, efficient, and noninvasive way to prevent and mitigate PCOS. This review deliberates on the variety of risk factors potentially involved in the etiology, prevalence, and modulation of PCOS, in addition to plausible therapeutic interventions, including miRNA therapy and the eubiosis of gut microbiota, that may help treat and manage PCOS.

Metabolic and Endocrine Agents · Insulin Sensitizing Agents

Inositol is an effective and safe treatment in polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials

Greff D et al., 2023 Reprod Biol Endocrinol Open Access

Metformin is the gold standard insulin sensitizer, which is widely used to treat insulin resistance in polycystic ovary syndrome (PCOS). However, metformin may induce gastrointestinal side effects. Inositols have long been debated as a potential alternative for metformin in treating PCOS. Therefore, the present systematic review aimed to evaluate the efficacy and safety of inositols in treating PCOS. The present systematic search was performed in CENTRAL, MEDLINE, and Embase from the inception until October 20th, 2021. Eligible randomized controlled trials (RCTs) included women diagnosed with PCOS and compared any inositols with metformin or placebo. Our primary outcome was cycle normalization, whereas secondary outcomes were body mass index (BMI), parameters of carbohydrate metabolism and clinical and laboratory hyperandrogenism. Results are reported as risk ratios or mean differences (MDs) with 95% confidence intervals (CIs). Twenty-six RCTs were identified, including data of 1691 patients (806 inositol, 311 with placebo, and 509 metformin groups). In patients treated with inositols, the risk (CI: 1.13; 2.85) of having a regular menstrual cycle was found by 1.79 higher than in the case of placebo. Moreover, the inositols showed non-inferiority compared to metformin in this outcome. In the case of BMI (MD = -0.45; CI: -0.89; -0.02), free testosterone (MD = -0,41, CI: -0.69; -0.13), total testosterone (MD = -20.39, CI: -40.12; -0.66), androstenedione (MD = -0.69, CI: -1,16; -0.22), glucose (MD = -3.14; CI: -5.75; -0.54) levels and AUC insulin (MD = -2081.05, CI: -2745.32; -1416.78) inositol treatment induced greater decrease compared to placebo. Inositol increased sex-hormone-binding globulin significantly compared to placebo (MD = 32.06, CI:1.27; 62.85). Inositol is an effective and safe treatment in PCOS. Moreover, inositols showed non-inferiority in most outcomes compared to the gold standard treatment; metformin. PROSPERO registration number: CRD42021283275.

Metformin directly inhibits androgen production in human thecal cells

Abstract

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Cite this article

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Metformin has direct effects on human ovarian steroidogenesis

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