Embryology, Mullerian-inhibiting Factor


Article Author:
Naiya Patel


Article Editor:
Anoosh Zafar Gondal


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Stephen Leslie
Karim Hamawy


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James Hughes
Beata Beatty
Nazia Sadiq
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Phillip Hynes
Tehmina Warsi


Updated:
7/14/2019 2:06:49 PM

Introduction

Mullerian inhibiting factor (MIF), also called the anti-Mullerian hormone (AMH) plays a significant role in sexual differentiation. It is produced by the Sertoli cells in male fetuses and signals the regression of the Mullerian ducts, fallopian tubes, and uterus. Androgens, which are secreted by Leydig cells, induce differentiation of Wolffian ducts into male internal and external genitalia. 

Development

Approximately around six weeks of gestation, the SRY gene is expressed on the Y chromosome, which initiates the formation of the testis. Mullerian inhibiting factor, testosterone, and insulin-like factor 3, which are all produced by the testis, control male sex differentiation.[1] Stimulated by follicle-stimulating hormone (FSH), Sertoli cells secrete the Mullerian inhibiting factor, which induces the regression of Mullerian or paramesonephric duct. The expression of Mullerian inhibiting factor prevents the development of female internal genitalia. Without Mullerian inhibiting factor, the Mullerian duct develops into the fallopian tubes, uterus, and upper vagina. In response to the luteinizing hormone (LH), Leydig cells produce testosterone, which is responsible for virilization of male internal genitalia, as well as the development of male secondary sex characteristics during puberty. Testosterone stabilizes the Wolffian or mesonephric duct, which differentiates into the epididymis, seminal vesicle, and vas deferens.[2] Testosterone is converted into dihydrotestosterone by 5-alpha-reductase. Dihydrotestosterone induces the differentiation of external male genitalia such as the prostate and penis.[3] 

Cellular

SRY gene, found on the Y chromosome, promotes the expression of SOX9, which plays a crucial role in the development of the testes. Under the influence of SRY and SOX9, the genital ridges differentiate into the testes. Testes are composed of transverse cords that contain Sertoli, germ, and peritubular myoid cells. Sertoli cells induce differentiation of Leydig cells via hedgehog signaling. Leydig cells are present in the interstitium, in between the transverse cords. Sertoli cells reinforce their own differentiation via prostaglandin D2 and FGF9 signaling by maintaining SOX9 expression. SOX9 also inhibits FOXL2, which prevents the differentiation of supporting cells into ovarian granulosa cells.[4] 

Molecular

Mullerian inhibiting factor is composed of two identical 70kDa subunits linked by disulfide bonds, which form a dimeric glycoprotein.[5][1] Mullerian inhibiting factor signals via two types of serine/threonine kinase receptors. The type 2 receptor is specific for MIF due to its similarity to the receptors of the transforming growth factor-beta (TGF-B) family. AMH shares a homologous C-terminus with the other members of the TGF-B family. When bound to its receptor, intracellular Smad molecules are signaled to enter the nucleus to function as transcription factors. The molecular identification of type 1 receptor is uncertain. The three types of type 1 receptors under research include alk2, alk3, and alk6. The type 1 receptor could potentially activate Smad molecules specific to bone morphogenetic proteins.[5]

Mechanism

Gonadotropins and androgens regulate the secretion of the Mullerian inhibiting factor. The gonadotropin-releasing hormone regulates LH and FSH secretion. FSH binds to its Sertoli cell receptor to stimulate the production of AMH.[6] From gestation to puberty, MIF is high, and testosterone is low in males.[2] LH binds to its Leydig cell receptor, causing the release of testosterone. Testosterone acts on its receptor on Sertoli cells and inhibits the production of MIF.[6] MIF gets stimulated by FSH but downregulated by testosterone. Therefore, in puberty, the increase in testosterone causes a decrease in MIF.[2] After gestation in females, ovarian granulosa cells of preantral and small antral follicles produce MIF. The level of MIF increases with an increase in the number of preantral and small antral follicles. The expression of MIF declines when the follicle reaches about eight millimeters in diameter.[7] 

Testing

The levels of the anti-Mullerian hormone are assessable via an enzyme-linked immunosorbent assay.[8] The Gen II AMH assay is the currently adopted standard. The Gen II AMH assay uses a more stable antibody to bind to AMH, which makes this assay more sensitive. There was undetectable cross-reactivity with inhibin A, activin A, FSH, and LH.[9] 

Pathophysiology

Persistent Mullerian duct syndrome is a type of male pseudohermaphroditism which is defined by the presence of female internal genitalia as well as male internal and external genitalia. This condition can also result from a mutation in the gene encoding MIF or a mutation in the MIF receptor. A mutation in the MIF gene will result in the lack of production of MIF. A mutation in the MIF receptor will result in the insensitivity of the Mullerian ducts to the hormone.[10][1] Lack of production or lack of response to MIF does not regress the Mullerian ducts and, therefore, these individuals have female internal genitalia. Individuals with persistent Mullerian duct syndrome present with a normal male phenotype; however, on examination, unilateral or bilateral cryptorchidism can be found.[8] 

Clinical Significance

Anti-mullerian hormone serves as a marker for ovarian reserve. It is used to determine the age at menopause and ovarian insufficiency. The number of primordial follicles is fixed at birth in females, but the follicles remain dormant until puberty. The dormant follicles do not produce AMH, but once recruited for development, AMH gets secreted by preantral and small antral follicles.[11] AMH rises with the number of growing follicles in the ovaries and reaches a plateau by twenty-five years. As age increases, the number of follicles decreases and, therefore, leads to a decline in serum levels of AMH. After twenty-five years of age, it gradually declines until menopause, eventually falling below detectable levels. It has an advantage as a biochemical marker compared to the measurement of ovarian steroid hormones, as there are no fluctuations with the menstrual cycle. Serum levels for a fertile woman range from 1.0 ng/ml to 4.0 ng/ml; under 1.0 ng/ml is considered low and indicates a diminishing ovarian reserve.[12] 

Measuring ovarian reserve predicts the chances of pregnancy in women, which is essential in couples dealing with infertility. Additionally, It has been useful in monitoring the fertility potential of women with cancer by measuring the serum levels, before and after treatment to assess the effect of chemotherapy on the ovaries. Serum AMH, which is secreted by granulosa cells of ovaries, can be used to diagnose ovarian granulosa cell tumors, monitor efficacy of surgery, and assess for recurrence. [9] In women with polycystic ovarian syndrome, AMH is two to three-fold higher than women with normal ovulation. AMH correlates to the number of preantral and small antral follicles. Patients with PCOS have a higher number of small antral follicles, resulting in an increased production of AMH. Patients using oral contraceptives have a decreased number of small antral follicles and, therefore, a lower level of AMH.[13]

Serum AMH is a marker of the function of Sertoli cells, while testosterone is a marker of the function of Leydig cells. In persistent Mullerian duct syndrome, serum testosterone is normal, and AMH is undetectable or normal. Normal levels suggest normal production and means that the mutation is present in the receptor of AMH. Low or undetectable levels suggest reduced production and that the mutation exists in the AMH gene. If levels of both testosterone and AMH are undetectable, this is suggestive of a lack of testicular function such as in anorchia or Klinefelter syndrome. Both are also low in mixed disorders of sex development because fetal hypogonadism results in dysfunction of Leydig and Sertoli cells.[6] 

The anti-mullerian hormone also plays a role as a biochemical marker for testing testicular dysfunction in cryptorchid males. The levels of AMH tend to be significantly lower in bilateral undescended testis compared to unilateral.[14]


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Embryology, Mullerian-inhibiting Factor - Questions

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A newborn with an uncomplicated birth and karyotype 46 XY has male external genitalia. The serum testosterone is 200 ng/dL and the level of Mullerian inhibitory factor (MIF) is undetectable. Physical examination reveals the presence of bilaterally undescended testes with empty scrotal sacs. During surgery to repair the undescended testicles, which of the following could be discovered?

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A female presents to her healthcare provider along with her 2-day-old male baby. She reports an uncomplicated pregnancy and birth. On examination, the child has male external genitalia but the scrotal sacs appear empty. Ultrasound reveals an undescended testis, uterus and fallopian tubes. Which of the following is consistent with this patient?

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A healthy 1-week old boy is brought in for routine immunizations. The mother states the delivery went well with no complications, and she is currently breastfeeding. She expresses serious concern about hypogonadism because her brother had Klinefelter syndrome. Karyotyping was done at 18 weeks gestation, and it showed 46, XY chromosomes. The temperature is 98.6 F, blood pressure is 85/55 mmHg, respiratory rate is 40 bpm, and the heart rate is125 bpm. The physical exam shows the presence of a normal-sized penis, and testes in scrotum bilaterally. Which of the following is true about the development of his genitalia?



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A 15-year-old male presents to the clinic for an annual check-up. Physical exam shows that the penis, scrotum, and testes are of adult size and shape. Pubic hair is coarse and dark. Which of the following processes occurs during puberty?



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Embryology, Mullerian-inhibiting Factor - References

References

Koopman P, The delicate balance between male and female sex determining pathways: potential for disruption of early steps in sexual development. International journal of andrology. 2010 Apr;     [PubMed]
Josso N,Clemente Nd, Transduction pathway of anti-Müllerian hormone, a sex-specific member of the TGF-beta family. Trends in endocrinology and metabolism: TEM. 2003 Mar;     [PubMed]
Xu HY,Zhang HX,Xiao Z,Qiao J,Li R, Regulation of anti-Müllerian hormone (AMH) in males and the associations of serum AMH with the disorders of male fertility. Asian journal of andrology. 2019 Mar-Apr;     [PubMed]
Dewailly D,Andersen CY,Balen A,Broekmans F,Dilaver N,Fanchin R,Griesinger G,Kelsey TW,La Marca A,Lambalk C,Mason H,Nelson SM,Visser JA,Wallace WH,Anderson RA, The physiology and clinical utility of anti-Mullerian hormone in women. Human reproduction update. 2014 May-Jun;     [PubMed]
Kelsey TW,Wright P,Nelson SM,Anderson RA,Wallace WH, A validated model of serum anti-müllerian hormone from conception to menopause. PloS one. 2011;     [PubMed]
Broer SL,Broekmans FJ,Laven JS,Fauser BC, Anti-Müllerian hormone: ovarian reserve testing and its potential clinical implications. Human reproduction update. 2014 Sep-Oct;     [PubMed]
Oh SR,Choe SY,Cho YJ, Clinical application of serum anti-Müllerian hormone in women. Clinical and experimental reproductive medicine. 2019 Jun;     [PubMed]
Josso N,Belville C,di Clemente N,Picard JY, AMH and AMH receptor defects in persistent Müllerian duct syndrome. Human reproduction update. 2005 Jul-Aug;     [PubMed]
Belville C,Van Vlijmen H,Ehrenfels C,Pepinsky B,Rezaie AR,Picard JY,Josso N,di Clemente N,Cate RL, Mutations of the anti-mullerian hormone gene in patients with persistent mullerian duct syndrome: biosynthesis, secretion, and processing of the abnormal proteins and analysis using a three-dimensional model. Molecular endocrinology (Baltimore, Md.). 2004 Mar;     [PubMed]
Josso N,Rey RA,Picard JY, Anti-müllerian hormone: a valuable addition to the toolbox of the pediatric endocrinologist. International journal of endocrinology. 2013;     [PubMed]
Hiort O, The differential role of androgens in early human sex development. BMC medicine. 2013 Jun 24;     [PubMed]
Grinspon RP,Rey RA, Anti-müllerian hormone and sertoli cell function in paediatric male hypogonadism. Hormone research in paediatrics. 2010;     [PubMed]
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