Biochemistry Objectives 50

1.Androgen biosynthesis:

  1. Testicular pathway: cholesterol is converted into pregnenolone via P-450scc pregnenolone is converted to progesterone via 3OH-SD, 5,4 isomerase  progesterone is converted to 17--progesterone by 17--hydroxylase  17--hydroxylase is converted to androstenedione by C17-20 lyase  androstenedione is converted to testosterone via 17-hydroxysteroid dehydrogenase  testosterone is converted to dihydrotestosterone via 5reductase-2
  2. Mechanism of stimulation: the process is stimulated via LH stimulation of P-450scc, the enzyme that catalyzes the conversion of cholesterol to pregnenolone

2.Estrogen biosynthesis:

  1. General pathway: follows the same pathway as testosterone, with the following caveats: androstenedione can form estrone (E1) via aromatase (19-hydroxylase) in adipose cells, testosterone can form 17-estradiol (E2) from aromatase in granulose cells, and DHEA can be 16-hydroxylated and modified to form estriol (E3). Note that E1, E2, and E3 can interconvert; E1 is oxidized E2, and E2 can be 16-hydroxylated to form E3.
  2. Location of LH stimulation (P-450scc): LH stimulation occurs in the thecal cells (initial formation of androgen)
  3. Location of FSH stimulation (aromatase): FSH stimulation occurs in the granulosa cells (formation of E2)
  4. Location of androstenedione aromatization: androstenedione aromatization occurs in the fetal liver/placenta (formation of E3)

3.Dihydrotestosterone:

  1. Enzyme that catalyzes its formation: 5--reductase
  2. Sites of production: produced mainly in peripheral tissues, though the testes secrete 50-100 μg per day
  3. Target tissues: targets the external genitalia (also prostate and genital skin) to induce male proliferation of external genitalia
  4. Role in benign prostatic hyperplasia: DHT induces the proliferation of the prostate, and with high levels of DHT in older men, the prostate will grow rapidly causing benign prostatic hyperplasia
  5. Role of 5--reductase-2 inhibitors in BPH treatment: since DHT is the main cause of benigh prostatic hyperplasia, treatment with 5--reductase-2 inhibitors will cause a lowered production of DHT and less stimulation of the prostate

4.Phenotypes, biochemistry, and pathophysiology of:

a.17-hydroxylase deficiency: inability to produce any of the sex hormones, and a hypogonadism due to decreased external genital differentiation stimulation

b.5--reductase-2 deficiency: inability to produce DHT, and a female external genital phenotype at birth that progresses to male hypogonadism as testosterone exerts its weaker effect to produce male external genitalia

c.Androgen receptor mutation: in XY patients, testicular formation occurs due to SRY region of the Y chromosome; however, since the body is insensitive to both testosterone and DHT, the patient makes no Wolffian structures, and the external genitalia is feminine.

5.Osteoporosis:

  1. Estrogen/androgen protection: estrogen acts as an inhibitor of both PTH and peripheral blood monocytes. Therefore, due to peripheral blood monocyte inhibition, estrogen causes a decrease in IL-1 and M-CSF, blocking osteoclast differentiation and protecting bone from resorption.
  2. Phytoestrogen nutritional value: phytoestrogens are controversial estrogen-like compounds found in foods that potentially have a beneficial effect due to their estrogen-like activity.