Intersex: Definitions, Causes, and Support

Formation Of External Genitalia

• After 6 weeks of intra-uterine life, Sexual differentiation begins in the genital tubercle and two genital swellings.
• The formation of human sex takes place at three levels:
  • Genetic Sex level [46 XX or 46 XY] 
  • Gonadal Sex level [Ovary or testes] 
  • Phenotypic level [vulva or Phallus]
• These three factors influence the internal genitalia of the human and the external genitalia of the human.
• Y chromosome has the Sex determining Region Y [SRY] or Testes Determining Factor [TDF].
• The presence of the TDF decides the sex of the baby. If it is present, then it is a male baby. If the TDF is absent, then it is a female. This is at the genetic level.

• The mesonephric duct, or the wolfian duct, forms the internal genitalia in a male.
• The paramesonephric duct or Mullerian duct forms the internal genitalia in a female.
• External  genitalia formation is under the influence of Androgens

Default/Basic Human Sexuality is Female unless androgens act upon them.

Also Read: Amniotic Fluid Dynamics

Mullerian Agenesis And Testicular Feminization Syndrome

• In Testicular Feminization syndrome, there is androgen insensitivity. Thus, they do not act on tissues; thus, the external genitalia remain feminine. In the periphery, these excess androgens are converted to estrogens (Androgens    Aromatase    → Estrogens)
•  This estrogen is then responsible for the formation of feminine breasts. However, the pubic & axillary hair remain absent due to the absence of androgenic action. Thus, the patient has perfect feminine features.
• TFS is distinguished from Mullerian Agenesis by
  • Absent axillary & pubic hair [clinical suspicion]
  • Karyotyping: 46 XY
  • USG reveals undescended testes (mostly in the abdomen, occasionally in the inguinal canal)
• Undescended testes are to be removed in TFS at the time of puberty to prevent the development of cancer.

Also Read: Mullerian Agenesis: Clinical Presentation and Treatment

Adrenal Steroidogenesis

21 Hydroxylase Deficiency causes a decrease in steroid hormones. This decrease in steroid hormones gives negative feedback to the hypothalamus, causing the release of ACTH and, thus, the release of sex hormones in the body.

Congenital Adrenal Hyperplasia (CAH)

It is also known as early-onset congenital adrenal hyperplasia. It occurs due to a deficiency of 21 Hydroxylase enzymes. It can be of three types:

Late-onset/adult-onset Adrenal Hyperplasia

• At puberty, there is an androgen spurt, and the girl presents with amenorrhea, masculine features, and even clitoromegaly.
• Treated  by long-term steroids
• Prevention
  • Start the steroid at the time of diagnosis of the next pregnancy

Also Read: Abnormal Uterine Bleeding Causes, Treatment, and Symptoms

Hermaphroditism

• Pseudohermaphrodite
  • Genetic male & phenotypic female: male pseudo hermaphrodite
  • Genetic female & phenotypic male: female pseudo hermaphrodite
• True Hermaphrodite
  • Male + Female karyotype
  • Male + Female gonads: ovotestis
  • Male + Female external genitalia

Gonadal Dysgenesis

Swyer Syndrome

• Gonadal dysgenesis in a boy
• 46 XY female
• No testes: no androgen. Therefore, external feminization will be seen.
• No testes: no MIF (Mullerian Inhibiting Factor): Mullerian structures are formed

Turner Syndrome

• The basic pathology is the presence of Streak gonads. Thus, there is less production of estrogens, leading to an infantile uterus with primary amenorrhea.
• Stigmata of Turner’s Syndrome
• Short stature 
• Shield chest 
• Low-set hair line 
• Lymphedema
• Cubitus valgus
• Normal intelligence
• Streak gonad
• Reduced estrogen
• Uterus small
• Primary amenorrhea
• Typical presentation: The patient presents with Short stature, Primary amenorrhea, and On USG has a hypoplastic uterus with streak gonads in Turner Syndrome.

Mixed Gonadal Dysgenesis

• This person will have a Male + female karyotype with Male + female gonads
  • U/L undescended testes: Not working
  • Contralateral streak ovary: Not working
• External genitalia: Female
• 1/3^rd of mixed gonadal dysgenesis have Turner phenotype
• 46 XX: 1 BARR body [normal female]
• 45XO: No Barr body → Turner Syndrome
• 46 XY: No BARR body [normal male]
• 47XXY: 1 Barr body in male: Klinefelter Syndrome
  • Tall stature 
  • Gynecomastia 
  • Obesity 
  • Azoospermia 
  • Infertility
  • Mental retardation
• Intelligence is normal in Turner syndrome
• Mental retardation is seen in Klinefelter syndrome
• More the number of X in genotype: more feminine
• XO (turner): female with one less X: less feminine female
• XXY (Klinefelter): male with one extra X: more feminine male (gynecomastia)

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