Reproductive Endocrinology Flashcards
What do the seminiferous tubules do?
They make up the bulk of the testes, and are involved in production of spermatozoa, they contain sertoli cells
What are sertoli cells?
Endocrine cells that produce inhibin and factors (ABP) that promote spermatogenesis, also called nurse cells
What are leydig/interstitial cells?
They are the major endocrine cells of the testes, they produce sex steroid hormones (primarily testosterone, but also DHT, estradiol, and others). They also produce activin
How are steroid hormones synthesized in the testes?
StAR protein in leydig/interstitial cells regulates cholesterol transfer within the mitochondria (rate limiting step, OMM –> IMM).
In mitochondria, cholesterol is converted to pregnenolone by P450SCC (catalyzes oxidation/hydroxylation).
Pregnenolone is translocated to the smooth ER for conversion to testosterone (either through progesterone –> 17-OH progesterone –> androstenedione –> testosterone) or (17-OH pregnenolone –> DHEA –> androstenedione –> testosterone).
What is the key enzyme for converting progesterone/pregnenolone?
17 alpha hydroxylase
What converts testosterone to dihydrotestosterone?
5alpha reductase
What is testosterone?
The predominant androgen (hormone that influences the growth and development of the male reproductive system) produced by leydig cells
What is dihydrotestosterone?
DHT, the more active androgen form. In target tissues, testosterone is converted to DHT by 5 alpha reductase
Does DHT or Test have higher affinity to the receptor?
Bind to same receptor, but DHT has higher affinity
What is estradiol?
Predominant form of estrogen, also plays a role in male sexual function
How is estradiol produced?
Produced from androstenedione conversion to estrone/estradiol by aromatase
How is most of the estradiol in male circulation produced?
By other tissues enzymatic conversion of testicular and adrenal-secreted androgen and estrogen precursors by aromatase in the brain, testes, adipose tissue
What are the main functions of Test and DHT?
- Differentiation of internal and external reproductive system during fetal development
- Growth of male reproductive system organs during puberty
- Stimulation of growth of skeletal muscles, and growth of epiphyseal cartilaginous plates
- Promotes libido, spermatogenesis in sertoli cells (paracrine effects)
- growth of larynx, hair growth, sebacious gland activity, social and behavioural changes
What does HcG do to promote testosterone secretion in fetal development?
It is secreted by the placenta during pregnancy to stimulate testosterone secretion from the fetal testes/fetal leydig cells, then stimulation of androgens stops from birth to 10-12 years of age, the testosterone increases with puberty, and gradually declines around 40-50 years of age
How does testosterone stimulate growth of skeletal muscles?
Enhances GH effects to increase IGF-1, also has independent anabolic effects, causes pubertal growth spurt
What is the function of estradiol in the male reproductive system?
Involved in male sexual function, and role in promoting pubertal growth spurt
How much of testosterone is bound by proteins in circulation?
60% bound by sex hormone binding globulin (produced in liver), 38% bound weakly to albumin (more bioavailable), 2% free in circulation
What is the signal transduction pathway for androgens?
Free T or DHT enters the cell, and in many tissues T is enzymatically converted by 5areductase to DHT. DHT or T bind to the same intracellular androgen receptor, which is a cytosolic/nuclear receptor (part of the steroid hormone family). Testosterone/DHT binding causes the release of HSP and chaperone proteins, causing receptor to form a homodimer with another complex, then the homodimer is translocated to the nucleus. This binds to androgen response elements in DNA and interacts with coactivators to initiate transcriptional activity
What is the cell surface signaling pathway for androgens?
Testosterone can bind to SRC –> activates MAPK (–> ELK-1 and CREB) or AKT (inhib FOXO and Bad). MAPK and AKT can also phosphorylate the AR nuclear receptor
What is the hypothalamic-pituitary-gonadal axis?
Hypothalamus secretes gonadotropin-releasing hormones, which travels to anterior pituitary through the hypophyseal portal system. Gonadotrophs release LH and FSH, which travel to the blood stream and affect gonadal function by promoting sex hormone production and gametogenesis
What are the effects of LH on the testes?
Stimulate the leydig cells to produce and secrete testosterone (which enters the circulation, and also acts via paracrine signaling to promote spermatogenesis)
What are the effects of FSH on the testes?
Stimulates testicular growth and acts on sertoli cells to enhance production of ABP (similar to sex hormone binding protein), ABP indirectly promotes spermatogenesis and sperm maturation by making androgens more soluble/very locally concentrated
What are inhibins and activins?
Members od the transforming growth factor beta superfamily ligands
What do inhibins do?
They inhibit the release of FSH from the pituitary.
What are inhibins produced by?
They are produced by sertoli cells in males, and the granulosa cells and corpus luteum in females. They are heterodimers made up of an alpha subunit + one of the two beta subunits
What do activins do?
They augment GnRH mediated release of FSH
What are activins produced by?
The leydig cells in males, granulosa cells and corpus luteum in females. Dimers made up of two beta subunits
What type of receptors are the LH and FSH receptors?
GPCR Galpha s: increase AC and cAMP
What feedback is there in the hypothalamic-pituitary-testes axis?
T, E2, DHT, inhibin inhibit GnRH, FSH, and LH secretion