1. Congenital adrenal hyperplasia
  2. Summary of consequences of deficiencies of some enzymes in the steroidogenic pathway
  3. Physiologic principles in the diagnosis of disorders of sexual differentiation

1. Congenital adrenal hyperplasia (CAH)

The two most important causes include:

  • 21 hydroxylase deficiency (commonest)
  • 11-beta hydroxylase 1 deficiency

Pathogenetic sequence:

  1. Block in synthesis of glucocorticoids and or aldosterone
  2. Increase in ACTH (as a result of loss of negative feedback effects of cortisol)
  3. Compensatory bilateral adrenal hyperplasia
  4. The block remains
  5. Increased synthesis of adrenal androgens

Salt loss and Addisonian crises with severe deficiency of 21 hydroxylase (salt losing form of CAH) accompanied by adrenogenital syndrome in newborns (males as well as females). Screening a newborn for possible congenital adrenal hyperplasia is done by estimating serum 17- hydroxyprogesterone. If it is elevated then it should be confirmed by estimating aldosterone and cortisol.

Manifestations in females:

  • With mild deficiency of 21 hydroxylase, the main consequence of clinical significance may be virilization at the time of birth (simple virilizing form of CAH)
  • Precocious pseudopuberty
  • Nonclassic CAH (late onset): virilization in postpubertal females

Clinical presentation depends on severity of deficiency:

  1. Salt losing form – with possible Addisonian crises
  • Ambiguous genitalia at birth in genetic females (female pseudohermaphroditism); adrenogenital syndrome
  • Precocious pseudopuberty or accentuation of male secondary sex characteristics in males
  • Virilization in postpubertal females
Enzyme Consequences of deficiency Cholesterol desmolase (side-chain cleavage enzyme) Fatal in utero as no steroid hormones can be synthesized Steroidogenic acute regulatory protein (STAR) This enzyme is not expressed in the placenta, and its deficiency has been described to be in some cases compatible with life. STAR is expressed in the adrenal cortex, testes and ovaries and is needed to transport cholesterol to the inner mitochondrial membrane in these tissues. STAR deficiency results in congenital lipoid adrenal hyperplasia. 3-beta hydroxysteroid dehydrogenase (type 2) Rare; this isoform is expressed in the fetal zone of the adrenal cortex and the gonads but not in the placenta. It is characterized by deficiency of cortisol, aldosterone and neither estrogens nor testosterone can be synthesized. In genetic males, the result is development of female external genitalia. Affected infants typically present with salt losing crises. 17α- hydroxylase (CYP17) Rare, no sex hormones, female genitalia develop regardless of genetic sex, characterized by an increase in plasma corticosterone, hypertension & hypokalemia 21 hydroxylase (CYP21) 95% congenital adrenal hyperplasia is due to deficiency of this enzyme; however, manifestations vary depending on severity of enzyme deficiency.    

Summary of Consequences of deficiencies of some enzymes involved in steroidogenesis in the adrenal cortex:

  • Basic principles of diagnosis of disorders of sexual differentiation: These are the most important facts one needs to know in order to understand and diagnose disorders of sexual differentiation.
  1. For our purposes, it is reasonable to think of development of female internal and external genitalia as a default genetic program in intrauterine development regardless of genotype.
  • However, the development of normal ovaries from the bipotential gonad requires the presence of 2 normal X chromosomes and the absence of the sex-determining region of the Y-chromosome (SRY). Several genes are required for the development of ovaries – therefore, development of ovaries should not be thought of as a default pathway.
  • A functional SRY gene, whether on the Y chromosome (normal), or ‘hiding’ in a X chromosome, dictates the formation of embryonic testes.
  • The differentiation of the gonadal ridge may be limited by deficiency of factors such as steroidogenic factor (SF-1), a nuclear receptor involved in transcriptional regulation of many genes including those need for steroidogenesis in the ovary and the testes.
  • Embryonic testes may or may not be functional. Functional embryonic testes secrete testosterone (Leydig cells) and Mullerian Inhibiting Substance (or Polypeptide, MIS or

MIP, from Sertoli cells).

Enzyme Consequences of deficiency   Three types of presentations are described: classic (salt-losing form) of CAH; simple virilizing form of CAH; and non-classic (late onset) form of CAH. 11β- hydroxylase (CYP11B1) Cortisol deficiency; virilization due to excessive synthesis of adrenal androgens; hypertension due to mineralocorticoid activity of high levels of 11- deoxycorticosterone    

Like in the adrenal cortex, steroidogenic acute regulatory protein (STAR) is expressed in the gonads and is required for normal synthesis of steroid hormones. As for intrauterine development, this is particularly important in males because embryonic testes produce testosterone.

  • Placenta does not express STAR and still synthesizes progesterone. Since STAR deficiency, at least, in some cases is compatible with life, it is likely because some of the progesterone from the placenta is channeled into other sites of steroidogenesis (fetal zone of the adrenal cortex, definitive adrenal cortex, testes and ovaries) and serves as the starting point for steroidogenesis. This mechanism potentially provides partial compensation for STAR deficiency.
  • With normal androgen receptors, testosterone

(T) induces the development of ‘male internal genitalia’ (epididymis, vas deferens, seminal vesicles) from the Wolffian duct (mesonephric duct).

  • MIS (MIP) acts in a paracrine fashion and induces regression of the ipsilateral Mullerian duct. In the absence of MIS (MIP), Mullerian ducts develop into Fallopian tubes, uterus, uterine cervix and the upper third of the vagina. The lower one third of the vagina forms in the absence of the actions of dihydrotestosterone (DHT) on the pelvic part of the definitive urogenital sinus.
  1. DHT, formed from T by the action of testosterone 5-alpha reductase (type 2), is required for the development of male external genitalia from the urogenital sinus into (growth of the male phallus, urethra, complete fusion of labioscrotal swellings to form the scrotum). Of course, the concentration of androgen receptors (AR) and their sensitivity to androgens should be normal for this to happen. The formation of DHT occurs inside target cells.

Type 2 5-alpha reductase predominates in the genital tract, and the isoform of the enzyme in the pilosebaceous unit is type 1. Finasteride is a more

potent inhibitor of the type 2 5-alpha reductase; however, finasteride has also been used in the management of hirsutism in females.

  1. T and DHT mediate their effects via the same AR. DHT-AR complexes are more stable. This explains why DHT is biologically the most potent androgen.
  1. The embryonic ovary does not produce any hormones, and estrogens are not required for intrauterine development of female internal or external genitalia.
  1. The critical period of differentiation of genitalia in intrauterine life is 8-12 weeks. T synthesis by the Leydig cell during this time is under the control of hCG (LH receptor). After

mid-gestation, fetal pituitary LH modulates fetal T synthesis and affects the growth of the differentiated penis.

  1. Genetic sex – male (46 XY), female (46 XX); gonadal sex (male – if testes are present; female – if ovaries are present); phenotypic sex – based on external genitalia – male, female, ambiguous.
  1. Gender assignment at birth is based on external genitalia (male; female; ambiguous)
  1. Gender identity: Identification of self as male or female. This is affected by one’s perception of his/her genitalia in comparison to others, how the child is raised (as female or male). The size of the phallus is a particularly important determinant.

When all of this is considered along with mechanisms involved in puberty and the actions of sex hormones, then we have most of the factual premises needed for understanding the phenotype in most disorders of sexual differentiation and therefore diagnosing them.

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