Müllerian inhibiting factor

**Source and genetics** - Fetal Sertoli cells produce MIF/AMH. SOX9, which is downstream of SRY on the Y chromosome, drives its expression. The gene is AMH on chromosome 19p13, and the receptor is AMHR2, a serine/threonine kinase receptor. - MIF belongs to the TGF-β superfamily. - Secretion begins around week 7–8 of gestation. This is before the Müllerian ducts regress, which is complete by about week 10.

**Normal male differentiation (3 hormones)** - Sertoli cells secrete MIF, which causes ipsilateral Müllerian duct regression. Failure to regress leaves a uterus, tubes, and upper vagina. - Leydig cells secrete testosterone, which acts through the Wolffian (mesonephric) ducts. These become the epididymis, vas deferens, seminal vesicles, and ejaculatory duct (**SEED**). - Dihydrotestosterone (DHT), made from testosterone by 5α-reductase, drives development of the external genitalia (penis, scrotum) and the prostate.

**Normal female development** - Without SRY there is no MIF, so the Müllerian (paramesonephric) ducts persist. They form the fallopian tubes, uterus, cervix, and upper 2/3 of the vagina. - The Wolffian ducts regress because there is no testosterone. - The lower 1/3 of the vagina comes from the urogenital sinus. - Postnatally, granulosa cells of small preantral and antral follicles produce AMH. Serum AMH reflects ovarian reserve. It is high in PCOS and low in diminished ovarian reserve and approaching menopause. It is also a tumor marker for **granulosa cell tumors**.

**Clinical correlations** - **Persistent Müllerian duct syndrome (PMDS):** This is a 46,XY disorder with normal male external genitalia and normal testosterone and DHT. It is caused by a mutation in AMH or AMHR2. Patients have a uterus and fallopian tubes in addition to testes. It often presents as cryptorchidism or as an incidental finding during inguinal hernia repair. The risk of testicular malignancy is increased. - **Androgen insensitivity syndrome (46,XY):** MIF is present, so there is no uterus, tubes, or upper vagina. The vagina ends blindly. External genitalia are female because of the androgen receptor defect. Testes are intra-abdominal or inguinal, and testosterone and LH are elevated. - **5α-reductase deficiency (46,XY):** MIF and testosterone are normal, so there is no Müllerian structure. DHT is deficient, so the external genitalia are ambiguous at birth. Virilization occurs at puberty. - **Swyer syndrome (46,XY gonadal dysgenesis):** There is no functional testis, so no MIF and no testosterone. Patients have a female phenotype with a uterus and streaks of gonadal tissue. The gonads need to be removed because of malignancy risk. - **Müllerian agenesis (Mayer-Rokitansky-Küster-Hauser syndrome):** 46,XX with normal ovaries and normal secondary sexual characteristics. The uterus and upper vagina are absent, and the cause is not MIF excess. - **Testicular dysgenesis or anorchia:** Low AMH helps confirm absence of functional testicular tissue in a child with bilateral cryptorchidism.

**High-yield tips** - MIF works ipsilaterally. In ovotesticular DSD or mixed gonadal dysgenesis, a hemiuterus may be present on the side of a dysgenetic gonad or streak. - MIF is made by Sertoli cells, not Leydig cells. A Leydig cell defect lowers testosterone but does not cause a retained uterus. - Mnemonic: **S**ertoli cells **S**uppress the **M**üllerian ducts. **L**eydig cells make **T**estosterone, which supports the Wolffian ducts.