18. Disorders of Sexual Development

“ We were working on puberty quote, but it’s not fully-developed yet.”

18.1 Introduction

  • Genetic sex is determined at fertilization by the genetic content of the sperm cell.

  • Gonadal sex (ovary vs. testes) is determined by hormones, as shown below:




TDF (testis-determining factor) is a protein encoded by sex-determining region Y (SRY) gene located in Y chromosome.



The following hormones are secreted by the testes:


Male internal accessory system

(e.g., epididymis, ductus deferens)

No male internal accessory system

Testosterone converted to dihydrotestosterone (DHT) by 5α-reductase

Male external genitalia

Female external genitalia

MIF (Müllerian-inhibiting factor)

Primordial uterus and fallopian tubes degenerate

Uterus, fallopian tubes and upper vagina

Note: Complete female sexual development requires absence of all the above-mentioned factors/hormones: TDF, testosterone, DHT, and MIF. In a rare case of loss-of-function mutation in SRY gene, there is absence of all the above-mentioned hormones/factors (leading to female internal and external organs in an XY genotype fetus). They also have failure of ovaries to develop, resulting in streak gonads (ovaries). This is called gonadal dysgenesis (a.k.a. Swyer syndrome).

18.2 Disorders of Embryonal Sexual Differentiation

Underlying condition


Male internal organs

External organ

Müllerian structures (uterus, fallopian tube, and upper part of vagina)

Complete androgen insensitivity syndrome in genetic males (XY-genotype)a

As TDF is working, testes are present, and ovaries are absent.

But DHT-dependent testicular descent may not occur, resulting in cryptorchidismc

No male internal organ

Female external genitalia (blind vaginal pouch)d

None (no uterus, no tubes, and no upper part of vagina)

Absolute testosterone deficiency due to 17-alpha hydroxylase deficiency in genetic males (XY-genotype)b

5-Alpha reductase deficiency (autosomal recessive disorder) in genetic males (XY genotype) e

Male internal organs are present (as the testosteronedependent process is preserved).

Müllerian agenesis (Mayer-Rokitansky-Kuster- Hauser syndrome) in XX fetusf


No male internal organs

Female external genitalia (blind vaginal pouch)

Virilization in females (due to exposure to excessive androgen, e.g., in congenital adrenal hyperplasia, androgen-secreting tumors)

Clitoromegaly (ambiguous genitalia)


aComplete androgen insensitivity syndrome is an X-linked mutation that results in defective androgen (testosterone/DHT) receptors that do not respond to androgens. Note: Genetic females (XX genotype) are carriers of this disease.

bIt is a type of congenital adrenal hyperplasia. Note: In genetic females (XX genotype), deficiency of estrogen (due to decreased conversion of testosterone into estrogen) leads to failure/delay of sexual development (e.g., primary amenorrhea with ultrasound [US] revealing uterus).

a,b Presentation: an apparently normal phenotypically female fails to have menarche, and is found to have a blind vaginal pouch.

cGonadectomy is recommended in cryptorchidism, as there is increased risk of dysgerminoma and gonadoblastoma. When to do gonadectomy? Wait until puberty (benefits of waiting until puberty for attainment of adult height likely outweighs gonadoblastoma risk).

dIn less severe forms, external genitalia can be ambiguous or have decreased virilization of male parts (e.g., partial androgen insensitivity syndrome, incomplete 5-alpha-reductase deficiency or mild 17-alpha hydroxylase deficiency). The less severe forms are harder to make a diagnosis.

e Mutation in 5-α-reductase

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Note: In genetic females (XX genotype) this has a subtler impact—e.g., delayed menstruation. Testosterone to estrogen conversion occurs in this case. In males, they might have blind vaginal pouch, or ambiguous genitalia with micro-penis.

fDefective embryogenesis resulting in absence of or very small Müllerian structure. They are phenotypically normal female with functioning ovaries and normal female hormonal levels. They present with amenorrhea (as no uterus) and a short vagina.

Defects of Müllerian Structures due to Abnormal Fusion

  • Septate/arcuate uterus

  • These are often incidentally found.

  • Bicornuate uterus

  • They may present with pelvic pain, endometriosis, hematocolpos (if uterus is obstructed), dyspareunia, etc.

  • Transverse vaginal septum

Dec 11, 2021 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on 18. Disorders of Sexual Development
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