Phar 508: Chemistry of Sex Hormones - Lecture 1

What is the precursor to all sex hormones?

Cholesterol (ABCD structure)

• Only difference is the position of the side groups

Where does hormonal biosynthesis start?

Stimulated in the brain

• Hypothalamus → Pituitary gland

What two locations does the actual biosynthesis occur?

• Gonads (ovaries - females, testes-males)

• Adrenal glands

What are the active forms of hormones?

Free, circulating hormones

What is the HPA axis?

Hypothalamic-pituitary-gonadal axis → The system that regulates hormones

• The HPA-axis includes both positive and negative feedback loops

What neurohormone is released/produced by the hypothalamus?

GnRH (gonadotropin releasing hormone)

What is GnRH and what does it do?

• GnRH is a decapeptide synthesized in the hypothalamus

• GnRH stimulates cells near the anterior pituitary to release other gonadotropins (LH & FSH)

What hormones (2) does the anterior pituitary release?

LH and FSH

What are LH and FSH? What are their structures composed of?

• LH = Luteinizing hormone; FSH = Follicle stimulating hormone

• They are heterodimers consisting of an alpha + beta subunit

  • Alpha subunits → identical

  • Beta-subunits → different

What are the male/female hormones?

• Androgens = Male hormones

  • Testosterone, Androsterone

• Estrogens = Female

  • Estradiol, Estriol, Estrone

What differentiates all the different sex hormones?

• The presence of an -OH or =O (ketone) group

• The side chains at C17 on the D-ring

Which cells types are associated with the ovary? Which receptors do they have?

Theca + Granulosa cells

• Theca cells → LH receptors (bind to LH)

• Granulosa → FSH receptors (binds to FSH)

Which cells types are associated with the testes? Which receptors do they have?

Leydig + Sertoli cells

• Leydig → LH receptors

• Sertoli → FSH receptors

Progesterone and testosterone are produced by which cells?

• Theca cells of the ovary

• Leydig cells of the testes

Estrone and estradiol are produced by which cells?

• Granulosa cells of the ovary

• Sertoli cells of the testes

Which enzyme is important in converting androgens to estrogens?

CYP19A1 (Aromatase)

Testosterone

• “testo” = testes

• “ster” = sterol

• “-one” = ketone

• Males produce 8.8-30.9 nmol/L

  • Females 0.4-2 nmol/L

• Biosynthesized throughout men’s life but peaks in 20s

What is the relationship between GnRH, LH, and FSH in males?

• Hormonal episodes spike 4-8x in 24 hours

• LH acts on Leydig cells within the testes

How is LH discharged? & why is this important?

LH has pulsatile spikes during the day, this is important bc:

• 1) High concentrations of testosterone are essential for spermatogenesis

• 2) Leydig cells becomes resistant/refractory to sustained high levels of LH

Estradiol

• estrane steroid ring system: estra-, from Greek, meaning "inspiration"

• -diol, a chemical term and suffix indicating that the compound is an alcohol with two OH-groups

• Female production >> Males

Progesterone

• Derived from PROGEstational STERoidal ketONEs

Estrogen production is primarily from…

The ovaries!

What are extra ovarian sources of estrogens?

Some expression in liver, adrenal glands, breast, placenta, and fat (becomes more important in postmenopausal state)

What are the three major estrogens?

Estrone (E1), Estradiol (E2), and estriol (E3)

Describe the process of progesterone production in the corpus luteum:

• The follicular theca cells luteinize into small luteal cells (thecal-lutein cells)

• The follicular granulosa cells luteinize into large luteal cells (granulosal-lutein cells)

• Both form the corpus luteum

• Progesterone is synthesized from cholesterol by both the large and small luteal cells upon luteal maturation

The Menstrual cycle

What are the roles of estrogen?

Women:

• Reproduction

• Bone health

• Metabolism

• Vascular health

• Brain function

Men:

• Fertility

• Bone health

• Metabolic health

• Libido and sexual desire

What are the roles of progesterone?

Women:

• Reproductive health

• Emotional regulation

• Brain and cognition

Men:

• Hormonal balance

• Central nervous system (CNS)

• Reproductive

• Cardiovascular health

What is the studied mechanism of signaling for steroidal/hormonal function?

Canonical (genomic) signaling

• Essentially, a hormone binds to its hormone receptor which can dimerize and bind to the hormone-response element on the DNA in promoter regions of target genes

  • Estrogen → binds to estrogen receptor (ER)

  • Progesterone → binds to progesterone receptor

  • Testosterone → binds to androgen receptor

What is the general structure of steroid hormone receptors?