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
How many oocytes are females born with?
1-2 million oocytes, each within a primordial follicle. This pool of oocytes (held in meiotic arrest) is depleted during childhood and adulthood via follicular atresia (apoptosis/breakdown)
How many oocytes are ovulated in total?
300-500
What are granulosa cells?
Support cells for oocytes (supply nutrients and produce signaling factors that affect oocyte development, plus activins and inhibins)
What type of receptors do granulosa cells have?
They have FSH receptors, no LH receptors. FSH promotes estradiol synthesis/secretion (via cooperation with theca cells)
What type of receptors do theca cells have?
They have LH receptors, no FSH receptors. LH stimulates production of androgens that are precursors for granulosa cells to convert to estradiol.
What is the corpus luteum?
The remaining granulosa and theca cells form this temporary endocrine structure after oocyte is ovulated. Produces progesterone primarily in response to LH (+ some estradiol in response to FSH and inhibins)
What promotes maturation of follicles?
In part FSH, several follicles mature per cycle
What happens during folliculogenesis?
Have proliferation of granulosa cells, which begin to express FSH receptors, estrogen receptors, and androgen receptors. Acquisition of theca cells, subpopulations begin to express LH receptors.
What happens to estradiol amounts as follicles mature?
They produce/secrete more and more estradiol
How do theca cells contribute to steroid hormone synthesis?
Synthesize androgen substrate (androstenedione). They have 17-a-hydroxylase and other enzymes for androgen synthesis, but lack aromatase (cannot synthesize estradiol).
How do granulosa cells contribute to steroid hormone synthesis?
Don’t express 17-a-hydroxylase, so cannot synthesize androgens –> require them from theca cells. Androgens from theca cells enter granulosa cells by diffision and provide the substrate for conversion to estradiol. Granulosa cells have aromatase
What are the effects of rising levels of estrogens as follicles mature?
There is negative feedback on pituitary FSH release. There is increase in FSH and LH receptors in maturing follicles.
Which follicle becomes the dominant follicle?
The follicle with the most granulosa cells = most FSH receptors. It is able to still grow despite decreasing levels of FSH due to negative feedback of estrogens on pituitary FSH release. This cell has the highest estradiol production.
What happens to the other nondominant follicles?
They undergo atresia (driven by apoptosis) because less FSH to support them/inhibit apoptosis
What do rising levels of estrogen cause?
They cause the uterine lining to thicken, and eventually cause the LH surge that promotes ovulation
What oocurs during ovulation?
There is an increase in proteolytic enzymes that make the follicular wall prone to rupture. Contraction of smooth muscle of the ovary aid in extrusion of the oocyte. Then the LH surge is required for maturation of the oocyte (meiotic resumption)
What are the functions of LH during ovulation?
LH surge required for meiotic resumption. Promote granulosa cells and theca cells that remain in ovulated follicle to differentiate into granulosa lutein cells and theca lutein cells to form corpus luteum. LH stimulates increased production/secretion of progesterone by corpus luteum
What occurs in the corpus luteum?
FSH-stimulated estradiol production -> androgens from theca lutein continue to be the substrate for conversion to estradiol by granulosa lutein cells. But progesterone is the major product of the corpus luteum. In response to LH, both granulosa and theca lutein cells produce progesterone. Granulosa cells now express LH receptors in addition to FSH receptors, as well as the enzymes for progesterone synthesis
How many genes need to be transcribed for glycoprotein hormones?
2, need an alpha (same for all) and a beta (unique for all)
Which hormones are glycoprotein hormones?
FSH, LH, TSH, and hCG
What are the differences in secretion patterns between FSH and LH?
They are synthesized by the same cell, but there is not much FSH peptide stored (amount secreted closely related to rate of synthesis, primarily regulated at the level of gene expression). For LH, you get release of pre-synthesized LH contained in storage granules, LH surge = regulation via stimulated secretion
What causes differential production and release of FSH and LH?
GnRH pulse frequency, levels/signaling of ovarian hormones (activin, inhibin, estradiol, progesterone, testosterone)
What do low frequency GnRH pulses favour?
FSH release
What do high frequency GnRH pulses favour?
LH secretion
What regulates the pulsatile release of GnRH?
The GnRH pulse generator relies on complex interactions between GnRH neurons and other neurons. Kisspeptin neurons play a key role in the regulation of pulsatile GnRH secretion, by integrating multiple nutrient, endocrine, and environmental signals
What are kisspeptins?
They are neuropeptides that are key regulators of GnRH secretion and the HPG axis
What is the positive feedback period of the HPO axis?
When estradiol levels reach a high threshold, estradiol promotes the LH surge by increasing the frequency of GnRH pulses, increasing pituitary sensitivity to GnRH (expression of GnRH receptors), and acting directly on the pituitary to stimulate LH secretion
What is the negative feedback of the HPO axis?
Progesterone reduces frequency of GnRH pulses. Ovarian hormones – estradiol, progesterone, testosterone, and inhibins inhibit GnRH release by the hypothalamus, and LH and FSH production release by the ant. pit.
What is the process of estrogen signaling?
Free estrogen diffuses into the cell. Can act on ER-a or ER-b receptors. When estrogen binds to a receptor, it dissociates from heat shock and chaperone proteins, forms a homodimer with another estrogenR complex, and translocates to the nucleus. Binds to ERE in the nucleus and interacts with protein coactivators and repressors to affect transcriptional activity
What is non-classical estrogen signaling?
Rapid non-transcriptional effects via cell surface receptors leading to MAPK activation
What are levels of GnRH, LH, and FSH during gestation?
High levels of all in childhood in both males and females.
Why are levels of LH and FSH slightly lower in male fetuses?
Male fetal gonads make testosterone, which lowers LH and FSH through negative feedback
What occurs to LH and FSH at birth?
Lose the maternally produced high estrogen levels (loss of neg feedback), so LH and FSH peak postnatally
What are levels of LH and FSH for most of childhood?
Low LH and FSH, inactive HPG axis
When do increased levels of adrenal androgens begin?
DHEA begins to rise years before the rise in gonadal sex steroids that occurs with puberty, persists until late puberty
What is one of the earliest events of puberty in males and females?
Onset of pulsatile release of GnRH, and in turn FSH and LH during REM sleep
What initiates the GnRH pulses at puberty?
Kisspeptin signaling has an important role
What are other changes characteristic of puberty that are mediated by increased secretion of gonadal sex steroids?
Secondary sex characteristics, growth spurt (estradiol stimulates IGF-1 production and promotes GH secretion; testosterone ehances GH effects to increase IGF-1). There are also changes in body composition and metabolism –> more adipose tissue in females, period of insulin resistance and increased insulin secretion
What are some endocrine system changes that occur with age?
Age-related decrease in GH levels begin after final height attained, IGF-1 levels also decline, T3 levels decline due to fibrosis of thyroid gland, pancreatic b cell function declines with ag
What occurs to FSH and LH during menopausal transition?
Initially levels are very high (decreasing inhibins and increasing activins). Progesterone is lower, so not as much negative feedback
What happens to estrodiol levels during perimenopause?
Levels fluctuate with FSH during perimenopause (variable levels, can be higher than in younger women)
What occurs late in the menopausal transition?
Impaired folliculogenesis, increased incidences of anovulation, estradiol levels fall, circulating androgens decrease with age (less dramatically).
After menopause, where are most estrogens produced?
Almost all estrogens are derived from peripheral tissues converting/aromatizing estrogens.
What is the predominant form of estrogen in postmenopausal women?
Estrone, which has a biological potency 1/3 that of estradiol
What are the functions of estrogens within the body?
Neuroprotection, maintenance of bone density, cardioprotection, growth and proliferation of breast tissue, influence on adipogenesis and adipose tissue metabolism (more subcutaneous adiposity), enhancement of insulin sensitivity and glucose tolerance
