Male Reproductive Endocrinology II Flashcards
The entire sequence of spermatozoa development requires around
60-70 days
This process (termed spermatogenesis) critically depends on support from the surrounding
Sertoli Cells
Within the basal compartment of the spermatic tubule (i.e. just beneath the basement membrane), spermatogonium undergo two mitotic divisions giving rise to
Three active Cells (Ap) and one resting cell (Ad)
The single resting AD cell will eventually serve a the progenitor for a later generation of
Sperm
The active Ap cells divide further to generate type B spermatogonia, which then give rise to a number of
Primary spermatocytes (PL)
These cells then enter the prophase of meiosis followed by the first
Reduction division
During this period, the complicated process of synapsis and chromosomal crossover occur. Within the adluminal compartment, we see the division of their daughter cells which are termed
Secondary spermatocytes
Their products, termed spermatids, contain 22 autosomes and either an
X or Y chromosome
The spermatids lie near the lumen of the tubule and are attached to the abutting Sertoli cells by
Specialized Junctions
In the final process of spermatogenesis, called spermiogenesis, spermatids undergo nuclear condensation, shrinkage of their cytoplasm, formation of an acrosome cap, and development of a
Flagellum
The spermatozoa are then extruded into the tubular lumen while most of the cytoplasm remains imbedded in Sertoli cells as
Residual Bodies
Movement of the spermtozoa into the epididymis is facilitated by fluid currents generated by the
Peritubular myoid cells
Contains the nucleus with its haploid chromosome content, and the acrosomal cap
Head of spermatozoa
Has concentrated hydrolytic and proteolytic enzymes that facilitate penetration of the ovum
Acrosomal cap
The middle peice,or body, of the mature spermatozoa contains the
Mitochondria
Contains stored ATP and pairs of contractile microtubules down its entire length
Principle peice of the flagellum
Cross-bridging arms contain
Dynein
An ATPase that transfers the energy of ATP into a sliding movement between the microtubules that imparts a flagellar motion to the spermatozoa
Dynein
For normal sperm production to occur, we must have normal function of the
HPT axis
Men with congenital GnRH, or FSH.LH deficiency are
Infertile
Therapeutic administration of GnRH or LH/FSH can restore
Spermatogenesis
Has the primary role of stimulating Leydig cells to produce testosterone
LH
Clearly stimulates Sertoli cells and this is likely the principal means by which it promotes spermatogenesis
Testosterone
Specifically, testosterone acts in conjunction with FSH to regulate
Sertoli Cell function
What are six examples of proteins that are upregulated in the Sertoli cells under the influence of FSH and testosterone?
- ) Inhibin
- ) AR
- ) Androgen-binding protein (ABP)
- ) Iron, copper, and Vitamin A BPs
- ) Growth factors
- ) Proteases and plasminogen activator
Modulates FSH release from pituitary gonadotrophs
Inhibin
Regulates specific gene expression in Sertoli cells in response to high levels of androgens
AR
Binds testosterone, DHT, and estradiol with high affinity and keeps their concentration high in the testes
ABP
Is also thought to facilitate the entry of androgens into sperm by endocytosis where androgens may influence spermatogenesi s
ABP
Concentrate their ligands in the testes where they promote sperm production
Iron, Copper, and Vitamin A BPs
Act in a paracrine manner to stimulate mitosis and inhibit apoptosis of spermatogonia
Growth factors like IGF 2, stem cell factor, epidermal growth factor (EGF), and TGF-β
Promote spermiation by facilitating (mechanically or chemically) the entry of spermatozoa into the lumen
Proteases and Plasminogen Activator
Spermatogenesis is further regulated in a paracrine fashion via local feedback loops between
Leydig, Sertoli, and peritubular cells
For example, testosterone from Leydig cells can stimulate the growth and differentiation of
Peritubular cells
These peritubular cells in turn secrete growth factors that stimulate
Sertoli Cells
Similarly, estradiol secreted from Leydig cells positively effects Sertoli cells and developing sperm, all of which express
Estrogen Receptors
The functional activity and shape of Sertoli cells changes during spermatogenesis suggesting that Sertoli cells respond to signals from
Sperm
One candidate sperm cell signaling factor is
Tumor necrosis factor α (TNFα)
Notably, Sertoli cells express
TNFα-receptors
In adults, plasma testosterone levels exhibit small pulses throughout the day corresponding to pulses of
LH
Much of the circulating testosterone is converted into the more potent androgen, DHT in target tissues (e.g., the prostate gland) via the enzyme
5α-reductase
DHT is more potent than testosterone in that it has a higher affinity for the
Androgen Receptor
Also secreted in large amounts by Leydig cells but possesses relatively weak intrinsic biological activity
Androstenedione
The major sources of estradiol and estrone in men
Testosterone and androstenedione
Only about 10% of these estrogenic compounds are directly secreted by the testes. Most of the estrogen in males is produced from circulating testosterone and androstenedione that become aromatized via
Aromatase
About 65% of circulating testosterone is bound to a liver-derived glycoprotein termed
Sex-hormone binding globulin (SHBG)
SHBG is identical in amino acid sequence to ABP of the Sertoli cells; SSBG and ABP differ in terms of their
Post-translational glycosylation
The remaining 33% of circulating testosterone is bound to
Serum Albumin
Also binds DHT and a substantial fraction of circulating estradiol
SHBG
Are not immediately biologically active but rather, serve as mobile reservoirs of androgen for peripheral tissues
Testosterone bound to SHBG
SHBG concentration is itself decreased by androgens and increased by
Estrogens
Hence, androgens are believed to increase their own biological availability by increasing the levels of
Unbound Hormone
Only about 1% of the total daily production of testosterone is directly
Excreted
Is believed to be initially responsible for stimulating testosterone production from fetal Leydig cells
Human Chorionic Gonadotropin (hCG)
After the sixth decade of life, plasma testosterone levels begin to decline primarily due to the gradual loss of responsiveness of Leydig cells to
LH stimulation
Note that the loss of testosterone-induced negative feedback allows
LH/FSH levels to rise during this period
Testosterone enters target cells by
Passive diffusion
If the target cell expresses CYP19, testosterone can also be converted into estradiol, a ligand for the
Estrogen Receptor (ER)
In the absence of ligand, the AR resides in the cytoplasm in an inactive state complexed with
Heat shock proteins
In the presence of DHT or testosterone, the receptor translocates to the nucleus, homodimerizes and then binds to specific DNA sequences termed
Androgen Response Elements
Crucial during fetal development for the masculinization of the Wolffian ducts into the epididymis, vas deferens, and seminal vesicles
Testosterone (not DHT)
Subsequently, the conversion of testosterone into DHT is required for the further fetal development of the
Penis, scrotum urethra, and prostate
At puberty, the hypothalamus begins to secrete increasing amounts of
GnRH
Are both required at puberty for the enlargement of the penis and for further development of the testes and seminal vesicles
Testosterone and DHT
Recall that development and growth of the testes at puberty also requires the orchestrated action of
FSH and LH
Is again required at puberty for the development of the scrotum and prostate, and to stimulate hair follicles to produce the typical male patterns of facial, pubic and body hair
DHT
Stimulates the production of sebum fro the sebaceous gland
-likely explains acne during puberty
DHT
Can promote male pattern baldness in the scalp of fully grown adults
DHT
Mediates enlargement of the larynx and thickening of the vocal cords during puberty that results in a deeper voice
Testosterone
First promotes bone lenghtening during puberty, but ultimately terminates linear growth by closing epiphyseal growth centers
Testosterone
Importantly, bone producing cells, termed osteoblasts, express both
AR and ER
Testosterone and estrogen potentiate growth hormone secretion and subsequently synergize with growth hormone by stimulating the production of various growth factors and cytokines in
Osteoblasts
Testosterone administration in adults results in nitrogen retention, indicating
Protein anabolism
Does not increase the muscle cell number, but rather it increases the size of the muscle fibers
Testosterone
In humans, the principle androgen-sensitive muscles are those of the
Pectoral region and shoulders
Increases plasma levels of low-density and very-low density lipoproteins (LDLs and VLDLs), while at the same time testosterone decreases circulating levels of high-density lipoproteins (HDLs)
Testosterone
Testosterone also promotes fat distribution in the
Upper body
Maintains normal red blood cell mass by stimulating erythropoetin synthesis and this matruration of erythroid precursors
Testosterone
Testosterone inhibits the hepatic expression of
Nuclear hormone carrier proteins
Occurs in both familial and sporadic forms and can be inherited as an autosomal dominant, autosomal recessive, or an X-linked trait
Congenital Gonadotropin Deficiency
The underlying inherited genetic defects can be manifold and include mutations in the
GnRH receptor, LHβ and FSHβ genes
Elevated levels of cortisol inhibit LH secretion in
Cushing’s syndrome
Along these same lines, fasting or critical illnesses (situations where cortisol levels go up and could remain high) can also cause
Gonadotropin Deficiency
The most common genetic cause of hypogonadism in men is
Klinefelter’s Syndrome
Characterized by abnormally small testes, elevated gonadotropin levels, impaired male sexual development, impaired spermatogenesis (azoospermia) and\ gynecomastia
Klinefelter’s syndrome
The unerlying genetic defect in Klinefelter’s syndrome is the presence of an
Extra X chromosome (47, XXY)
A variant of Klinefelter’s syndrome but is more rare
XX mle syndrome
In approximately 80% of 46, XX men, a fragment of the SRY has been translocated to the
X chromosome
In 46, XX men lacking Y chromosome fragments, we see the presence of a duplicated
-indicates autosomal mechanism
SOX9 gene
A downstream target of SRY-mediated testicular development
SOX9
Severe genetic defects in the LH receptor can result in an autosomal recessive form of male psuedohermaphroditism in which 46, XY individuals have a
Female phenotype, blind ending vagina, and inguinal testes w/ no Leydig cells
Less severe LH receptor mutations are associated with variable degrees of impaired male sexual development and
Low testosterone
The most common cause of acquired testicular failure in adults is
Viral Orchitis
Can be acquired from infection by the mumps virus, echovirus, lymphocytic choriomeningitis virus as well as members of the group B arboviruses
Viral Orchitis
Cyproterone, the antifungal agent ketoconazole, antiepileptic drugs phenytoin and carbamazepine, or ingestion of large amounts of ethanol, marijuana, heroin or methadone are examples of drugs that cause
Low testosterone
Inherited genetic defects in genes involved in androgen biosynthesis have been implicated in a number of
Male hypogonadal disorders
