The effect of Combined Oral Contraceptive Pill and Metformin on serum AMH, Clinical, Hormonal, Metabolic and Radiological outcomes in PCOS patients: ARandomized Trial

Justification for the conduct of the study:

Recently, high serum AMH levels have been proposed as a surrogate marker for defining polycystic morphology (PCOM) (1). However, the role of serum AMH as a marker for response to therapy in PCOS is underexplored. Several studies have found increased AMH levels in both serum[ (2) (3) (4) ] and follicular fluid (5) of women with PCOS. Another study has corroborated these findings, showing that the granulosa cells of polycystic ovaries have increased AMH mRNA expression (6).

It is well known to us that OCPs reduces circulating androgen levels through suppression of LH and stimulation of SHBG levels, while metformin acts by suppressing hepatic gluconeogenesis thereby reducing circulating Insulin levels which results in lower androgen production by theca cells. However controversial data exists on whether reducing serum AMH concentration is in concordance with reduction in number of preantral/ small antral follicles leading to improvement in menstrual irregularities as a consequence of better intraovarian hormonal mileu and folliculogenesis.

Till now, there has been only 1 RCT comparing the effect of OCPs vs Metformin on serum AMH among PCOS patients (7). Serum AMH concentration may better represent intraovarian follicular dynamics in PCOS as compared to other crude USG parameters like Antral follicle count and ovarian volume which are observer-dependent with high interobserver variability. Moreover, Transabdominal USG may miss pre-antral and small antral follicles, which forms the major pool for serum AMH secretion. In a country like India , TVS cannot be performed in all PCOS patients, especially in unmarried women, so AMH can serve as an alternative for diagnosis and also for monitoring response to therapy.

References:

1.     Teede HJ, Tay CT, Laven JJE, Dokras A, Moran LJ, Piltonen TT, et al. Recommendations from the 2023 international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Eur J Endocrinol. 2023 Aug 2;189(2):G43–64.

2.     Pigny P, Merlen E, Robert Y, Cortet-Rudelli C, Decanter C, Jonard S, et al. Elevated Serum Level of Anti-Mullerian Hormone in Patients with Polycystic Ovary Syndrome: Relationship to the Ovarian Follicle Excess and to the Follicular Arrest. J Clin Endocrinol Metab. 2003 Dec 1;88(12):5957–62.

3.     Pigny P, Jonard S, Robert Y, Dewailly D. Serum Anti-Müllerian Hormone as a Surrogate for Antral Follicle Count for Definition of the Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2006 Mar;91(3):941–5.

4.     Siow Y, Kives S, Hertweck P, Perlman S, Fallat ME. Serum müllerian-inhibiting substance levels in adolescent girls with normal menstrual cycles or with polycystic ovary syndrome. Fertil Steril. 2005 Oct;84(4):938–44.

5.     Pellatt L, Hanna L, Brincat M, Galea R, Brain H, Whitehead S, et al. Granulosa Cell Production of Anti-Müllerian Hormone Is Increased in Polycystic Ovaries. J Clin Endocrinol Metab. 2007 Jan;92(1):240–5.

6.     Catteau-Jonard S, Jamin SP, Leclerc A, Gonzalès J, Dewailly D, Di Clemente N. Anti-Mullerian Hormone, Its Receptor, FSH Receptor, and Androgen Receptor Genes Are Overexpressed by Granulosa Cells from Stimulated Follicles in Women with Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2008 Nov 1;93(11):4456–61.

7.     Panidis D, Georgopoulos NA, Piouka A, Katsikis I, Saltamavros AD, Decavalas G, et al. The impact of oral contraceptives and metformin on anti-Müllerian hormone serum levels in women with polycystic ovary syndrome and biochemical hyperandrogenemia. Gynecol Endocrinol. 2011 Aug;27(8):587–92.