Male Reproductive Endocrinology II Flashcards by Joel Glotfelty

The entire sequence of spermatozoa development requires around

60-70 days

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This process (termed spermatogenesis) critically depends on support from the surrounding

Sertoli Cells

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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)

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The single resting AD cell will eventually serve a the progenitor for a later generation of

Sperm

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The active Ap cells divide further to generate type B spermatogonia, which then give rise to a number of

Primary spermatocytes (PL)

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These cells then enter the prophase of meiosis followed by the first

Reduction division

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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

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Their products, termed spermatids, contain 22 autosomes and either an

X or Y chromosome

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The spermatids lie near the lumen of the tubule and are attached to the abutting Sertoli cells by

Specialized Junctions

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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

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The spermatozoa are then extruded into the tubular lumen while most of the cytoplasm remains imbedded in Sertoli cells as

Residual Bodies

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Movement of the spermtozoa into the epididymis is facilitated by fluid currents generated by the

Peritubular myoid cells

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Contains the nucleus with its haploid chromosome content, and the acrosomal cap

Head of spermatozoa

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Has concentrated hydrolytic and proteolytic enzymes that facilitate penetration of the ovum

Acrosomal cap

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The middle peice,or body, of the mature spermatozoa contains the

Mitochondria

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Contains stored ATP and pairs of contractile microtubules down its entire length

Principle peice of the flagellum

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Cross-bridging arms contain

Dynein

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An ATPase that transfers the energy of ATP into a sliding movement between the microtubules that imparts a flagellar motion to the spermatozoa

Dynein

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For normal sperm production to occur, we must have normal function of the

HPT axis

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Men with congenital GnRH, or FSH.LH deficiency are

Infertile

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Therapeutic administration of GnRH or LH/FSH can restore

Spermatogenesis

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Has the primary role of stimulating Leydig cells to produce testosterone

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Clearly stimulates Sertoli cells and this is likely the principal means by which it promotes spermatogenesis

Testosterone

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Specifically, testosterone acts in conjunction with FSH to regulate

Sertoli Cell function

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What are six examples of proteins that are upregulated in the Sertoli cells under the influence of FSH and testosterone?

1. ) Inhibin 2. ) AR 3. ) Androgen-binding protein (ABP) 4. ) Iron, copper, and Vitamin A BPs 5. ) Growth factors 6. ) 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

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

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