Pharmacology 3620 Lecture Notes - Lecture 40: Hypophyseal Portal System, Sertoli Cell, Anterior Pituitary
1 May 2018
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14. Drugs used to Manipulate Fertility
Learning Objectives
● Identify the most frequent therapeutic uses of estrogens, progestins, and androgens with
regards to female fertility
● Explain the mechanisms of action (to the extent that they are currently understood) of
contraceptive estrogens and progestins
● Explain the mechanism of action of the partial estrogen agonist, clomiphene, for the
induction of ovulation [SERM]
● Explain the mechanism of action of the therapeutic androgen, danazol, for the treatment
of endometriosis
● Explain the mechanism of action of phosphodiesterase-5 inhibitors for the treatment of
erectile dysfunction
The neuroendocrine system is controlled by the hypothalamus and pituitary gland
● Hypothalamus secretes GnRH into the hypophyseal portal system
○ GnRH is released in a pulsatile pattern
● GnRH acts on anterior pituitary
○ Produce LH and FSH
● LH and FSH acts on the ovaries and testes
○ Produce sex hormones
■ Estrogen
■ Testosterone
● Estrogen and testosterone feedback and inhibit the release of GnRH, LH, and FSH
● However, estrogen can potentially pituitary GnRH release
○ Depends on the time of the menstrual cycle which circulating concentration of
estrogen and the rate of its increase
LH and FSH act on “two-cell” systems in the gonads
● Ovaries
○ Thecal cells
■ Outside of the follicle
■ LH increase androgen synthesis
● The synthesised androgen then diffuse out of the thecal cells to
act on the nearby granuloma cells
○ Granulosa cells
■ Line the developing oocyte
■ FSH act to increase to activity of aromatase
● Aromatase acts on androgens to produce estrogen
● Testes
○ Leydig cells
■ LH increase testosterone synthesis
● Testosterone diffuse into the nearby sertoli cells
○ Sertoli cells
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■ FSH increase expression of ABP (androgen binding protein)
■ ABP binds to testosterone
● Testosterone-ABP complex stabilizes high concentrations of
testosterone required for spermatogenesis germinal epithelium
Sex hormones exert actions on target cells by binding intracellular receptors
● Circulating testosterone
○ Bound to SHBG or albumin
○ Gets delivered to target cells and diffuses across the membrane
● In cytosol, testosterone is converted to DHT (by 5-reductase)
○ DHT has higher receptor binding affinity and higher androgenic activity
● Homodimers of DHT binds to the androgen receptor (AR)
○ Gets transcription of testosterone dependent genes
Binding of an antagonist or agonist will promote a conformational change in hormone
receptor
● Promote the recruitment of co-receptor or co-activators
● This method allows ligand-ER complexes to recruit transcriptional co-repressors and co-
activators in a tissue selective manner
○ Get tissue selective action
○ Very useful for medication to take advantage of this pathway way
○ This is how SERMs works
Female reproductive cycle
● FSH and LH secretion increase
○ FSH promote the development of multiple follicles
■ Follicles start to secrete estrogen
● Dominant follicle develop
○ Secretes even more estrogen
● Increase in plasma estrogen negative feedbacks to decrease FSH secretion
○ Slight drop
● However, estrogen also exert a positive feedback effect on FSH and LH
○ This triggers the LH surge
● Ovulation occurs
○ Ovum is release
○ Corpus luteum is generated
● Corpus luteum secretes high amounts of estrogen and progesterone
○ Plasma estrogen and progesterone increase
○ FSH and LH secretion decrease (due to negative feedback)
● Corpus luteum degenerates
○ Plasma estrogen and progesterone decrease
Female fertility is limited to a short window of the reproductive cycle
● Sperm can survive vaginal environment for 4 to 6 days
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Identify the most frequent therapeutic uses of estrogens, progestins, and androgens with regards to female fertility. Explain the mechanisms of action (to the extent that they are currently understood) of contraceptive estrogens and progestins. Explain the mechanism of action of the partial estrogen agonist, clomiphene, for the induction of ovulation [serm] Explain the mechanism of action of the therapeutic androgen, danazol, for the treatment of endometriosis. Explain the mechanism of action of phosphodiesterase-5 inhibitors for the treatment of erectile dysfunction. The neuroendocrine system is controlled by the hypothalamus and pituitary gland. Hypothalamus secretes gnrh into the hypophyseal portal system. Gnrh is released in a pulsatile pattern. Lh and fsh acts on the ovaries and testes. Estrogen and testosterone feedback and inhibit the release of gnrh, lh, and fsh. However, estrogen can potentially pituitary gnrh release. Depends on the time of the menstrual cycle which circulating concentration of estrogen and the rate of its increase.
