Gametogenesis
• Gamete production
• Begins in utero and reinitiated with puberty
• Mitosis of germ cells
• Meiosis
– Primary gamete
– Secondary gamete
– Haploid gamete
• Different timing in males and females
MITOSIS
Germ cell proliferation
46 chromosomes
per cell (only two
shown here)
Embryo
Embryo
Secondary
spermatocyte
Reproductive adult
Sister
chromatids
FEMALE
Oögonium
46
(diploid)
Spermatogonia
Primary
spermatocyte
STAGE OF CELL DIVISION
MEIOSIS
DNA replicates but
no cell division occurs.
2 sets of 46
chromosomes
First meiotic
division
Primary gamete divides
into two secondary gametes.
23 chromosomes
duplicated
Second meiotic
division
Spermatids
develop into
Secondary gamete divides.
23 chromosomes
(haploid)
Sperm
One primary spermatocyte
yields 4 sperm.
Oögonia
First
polar
body
Secondary
oocyte
(egg)
(may not
occur)
Disintegrates
Egg released
from ovary at
ovulation
One primary oocyte
yields 1 egg.
FERTILIZATION
Zygote
Primary
oocyte
Sister
chromatids
Reproductive adult
MALE
Spermatogonium
From 1 primary spermatocyte, you get 4
sperm. Compare to the female where you
only get 1 mature egg from 1 oocyte.
Second polar body
disintegrates.
Unfertilized egg passes
out of body.
Figure 26-5 (9 of 9)
Spermatogenic Stage & Wave
• A spermatogenic wave is defined as the time it takes for the reappearance of the same stage within a given
segment of the tubule.
• Each stage of the wave follows in an orderly sequence along the length of the tubule. The distance between
the same stage is called the spermatogenic wave.
• Production of sperm in waves ensures that spermatozoa are produced continuously so that mature
sperm are always available.
• One tubule can contain numerous complete waves. Adjacent segments of the tubule communicate in some
unknown manner.
• Six stages of spermatogenic wave have been noted in man.
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Becky Stepan
Rose – Hellenkant – Physiology of Male Puberty
Six stages divided into four phases are needed to complete a wave of spermatogenesis
The temporal course of Spermatogenesis
The approximate 64 day cycle of the spermatogenesis can be subdivided into 4 phases that last differing lengths
of time.
Mitosis of the spermatogonia
First Meiosis
Second Meiosis
Spermiogenesis
16 days
24 days
A few hours
24 days
Totals ~64 days
Up to the primary spermatocytes
For the division of the primary spermatocytes to form
secondary spermatocytes.
For engendering the spermatids.
Up to the completed sperm cells.
Spermatogenesis is staggered so
that all developmental phases are
present at any one time.
•
•
•
•
spermatogonia to
spermatozoa: 64 days
high temperature today means
sperm anomalies in 2 months
Another staggering factoid:
 daily sperm
production: ~2 million
Spermatogenesis continuous
through lifespan but
production decreases with age.
*You could have sub-standard and
diminished infertility for up to 64
days after heat exposure such as
being a hot-tub for too-long. But
there is on-going continuous study
on this.
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Becky Stepan
Rose – Hellenkant – Physiology of Male Puberty
Hypothalamic-pituitary-testicular axis
ABP – binds to testosterone
and keeps local levels high
and hanging around the
seminferous tubule;
Inhibin is specific to FSH
release.
Epdidimys is the holding
area for the next ejaculate.
Male Reproductive Anatomy/Histology
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Becky Stepan
Rose – Hellenkant – Physiology of Male Puberty
The Sertoli Cell of your fellow Man
1. Provide Sertoli cell barrier to chemicals in the plasma
2. Nourish developing sperm.
3. Secrete luminal fluid, including androgen-binding protein.l
4. Respond to stimulation by testosterone and FSH to secrete paracrine agents that stimulate sperm
proliferation and differentiation.
5. Secrete the protein hormone inhibin, which inhibits FSH secretion from the pituitary. It is negative
feedback for FSH, but not LH.
6. Secrete paracrine agents that influence the function of Leydig cells.
7. Phagocytize defective sperm.
8. Secrete, during embryonic life, Muellerian inhibiting substance (MIS), which causes the primordial female
duct system to regaress.
9. Correction between the number of sertoli cells and daily sperm production.
Did you know that each Sertoli Cell supports a fixed number of germ cells by providing an environment within the
seminiferous tubules in which germ cells develop and by providing a physical and nutritional support for these
cells? There is a simple linear relationship between Sertoli cell number and daily sperm production.
The testes is like the adrenal gland but more…….
Effects of Testosterone in the Male
1. Required for initiation and maintenance of spermatogenesis (acts via Sertoli cells).
2. Decreases GnRH secreation via an action on the hypothalamus.
3. Inhibits LH secretion via a direct action on the anterior pituitary.
4. Induces differentiation of male accessory reproductive organs and maintains their function.
5. Induces male secondary sex characteristics ; opposes action of estrogen on breast growth.
6. Stimulates protein anabolism, bone growth, and cessation of bone growth.
7. Required for sex drive and may enhance aggressive behavior.
8. Stimulates erythropoietin secretion by the kidneys.
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Becky Stepan
Rose – Hellenkant – Physiology of Male Puberty
SUBFERTILITY/INFERTILITY: man does not have high fertility
• gamete
• accessory gland dysfunction
− improper fluid constituents [the appropriate fluid concentration level is important to make it
through the hostile environment of the vagin]
− glandular hyperplasia, cancer (prostate)
• anatomical problems [such as hypospadis]
− retrograde ejaculation
• endocrine problems
− reduced testosterone: hypothalamus-pituitary-gonadal axis
• erectile dysfunction
Sedentary Lifestyle, Heat & Sperm Fuction
• A significant relationship between scrotal temperature and sperm count has been established in recent
years.
• The sedentary lifestyle of men of all ages may impair the ability of the scrotum to thermoregulate.
• Men with more sedentary lifestyles or occupations have higher average scrotal temperature.
• In turn, an elevation of scrotal temperature to normal core body temperature results in a failure of
spermatogenesis. This effect is probably at its worst in paraplegic men.
• A study of normal young men showed that an elevation of scrotal temperature by as little as 0.7C for 75%
of the working day was sufficient to significantly impair semen quality.
• A rise in scrotal temperature may increase the number of abnormal sperm, decrease sperm motility and/or
decrease the number of sperm in the ejaculate.
• These effects may lead to impaired fertility and can affect implantation and early embryo development as
the miscarriage rate is significantly elevated in female animals after mating with an "affected" male.
Temperature Sensitivity of Human Spermatogonia and Spermatocytes in Vitro
• The number of differentiated germ cells such as spermatids and spermatozoa cultured at 37d`C was
significantly smaller than that cultured at 31 degree. The number of spermatogonia and resting primary
spermatocytes was not significantly different between these two temperatures, but the functional ability of
DNA synthesis in these cells was significantly lower at 37d`C
Failure of Testicular Descent
• Cryptorchid - unilateral or bilateral
• bilateral - normal sexual phenotype, libido, androgens, but sterile due to relatively high intra-abdominal
temp.
• May not be sterile if testes in inguinal canal
• Mechanisms to maintain lower temp in testes
 dartos muscle in scrotum
 increases/decreases surface area
 increases/decreases thickness of skin
 cremaster muscle in spermatic cord - raises or lowers testes
 pampiniform plexus - countercurrent mechanism
 temperature receptors in scrotal skin can elicit responses that tend to lower whole body temp
(sweating, panting)
Andropause: no real hallmark feature “diminished ability to act on sexual impulse”
1)Decrease in testicular function
 correlated with loss of spermatocytes,
 decrease of testosterone production
 compensatory increases in secretion of GnRH and gonadotropins (FSH and LH)
2) Symptoms
 +/-Sexual dysfunction
 Weight gain due to metabolism shifts, reduced activity
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Becky Stepan
Rose – Hellenkant – Physiology of Male Puberty
3)Palliative Treatments
 sleep, eat well, exercise
 hormone replacement, growth hormone therapy
 Viagra-like drugs
Mechanism of Andropause
• Low testosterone levels
• Loss of hypothalamic sensitivity
• Testicular Defect
• SHBG Level Increase
• Circadian Rhythm Dysfunction
Androgens & Other Reproductive Drugs
• Androgens
• Androgen Receptor antagonists
• Gonadotropin Releasing Hormone agonists
• GnRH antagonists
• 5-alpha reductase inhibitors (DHT)
• Phosphodiesterase 5 inhibitors
Trying to wipe out testosterone
production by stimulating the
continuous amount of GnRh agonists.
Completely reverse the response by
giving a continuous bolus.
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Becky Stepan
Rose – Hellenkant – Physiology of Male Puberty
Action of Androgens
Testosterone Affects
• Androgenic Effects
Muscle
– Seminal vesicle
Seminal Vesicle
– Prostate
Epididymis
– Genital tract
Bone
– External genitalia
– Hair growth patterns
– Voice Change
• Anabolic Effects
– Positive nitrogen balance
– Bone growth and closure of epiphysis
– Sodium and water retention
Pharmacokinetics of Testosterone Proprionate
• Absorbed readily
• 1st pass metabolism
• Esterification retards absorption
• Bound to SHBG
• Oxidation & Reduction in Liver
− Weak or inactive metabolites
− Metabolites conjugated
Pharmacokinetics of Methyltestosterone
• Absorbed readily
• 1st pass metabolism
• Esterification retards absorption
• Transdermal patch, gel, transbuccal
• 17a-alkyl substitution
− Retards metabolism
− Orally active
− Hepatotoxic
• Bound to SHBG
• Oxidation & Reduction in Liver
− Weak or inactive metabolites
− Metabolites conjugated
Dihydrotestosterone Affects
Prostate
External Genitalia
Skin
O
CH 3
OCCH 2 CH 3
O
Testosterone propionate
CH 3
O
OH
CH 3
Methyltestosterone
Uses for Testosterone Replacement
Adverse Effects of Using Androgens
• Hormone Replacement
• Growth interruption (premature bone closure)
− Hypogonadism (low androgen production)
in growing youth
− Hypopituitary
• Priapism
• Anabolic Effects
• Sodium & water retention
− Trauma, debilitating disease
• Jaundice
− Enhanced athletic performance
• Hepatic carcinoma
• Hypogonadism upon cessation due to long-term reduction in
hypothalamo-pituitary-gonadal axis – shutdown of the normal axis.
• Aggressive behavior
• Urinary obstruction
Medical Castration – Use:
• Androgen receptor antagonists
Androgen Antagonists
• GnRH agonists
Flutamide, Bicalutamide, Nilutamide
• GnRH antagonists
• Nonsteroidal receptor antagonist
• Advanced prostate cancer
• Side Effects: Gynecomastia (because there is a block of androgen function), methemoglobinemia, hepatoxic
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Becky Stepan
Rose – Hellenkant – Physiology of Male Puberty
Androgen Antagonists
Spironolactone (Androgen Antagonists) – Used Primarily as diuretic
• Weak receptor antagonist; Inhibits CYP450
• Can also block Hirsutism (hair development) and androgen dependant acne
GnRH (LHRH) Agonists
• Gonadorelin = synthetic GnRH
− Used for functional assessment of gonadal response
• Leuprolid, Goserelin, Triptorelin, Histrelin, Nafarelin
− Used for castration to treat cancer
− Uterine fibroid treatment for women
− Ovarian stimulation
− Precocious puberty
− More potent
− Slower metabolism
• Administation of GnRH (LHRH) Agonists
− Pulsatile administration  Induce release of FSH & LH – this promotes the conditions above such as
precocious puberty, and uterine fibroids.
− Continuous administration  causes an initial hypersecretion of LH and FSH flair (hence
Testosterone increase) followed after ~ 10 d by desensitization of the pituitary and suppression of
LH and FSH.
GnRH Antagonists
• Degarelix
− prostate cancer, BPH,, assisted reproduction use under investigation
• Ganirelix, Cetrorelix
− Used for assisted reproduction along with other IVF drugs
The major point: Major difference with GnRH antagonists is that there is not an initial LH/FSH hypersecretory
phase.
5 alpha reductase inhibitors for inhibiting DHT
• Benign prostatic hyperplasia
• Male patterned baldness
• Finasteride  BPH, male pattern baldness
• Dutasteride  BPH
• Use in prostate cancer prevention is under scrutiny -although PSAs decreased early increase in high-grade
Cancer in treatment arm compared to placebo arm.
• Advice from Medical Letters is not to use for prostate cancer at this time.
Assisting the Erection and Ejaculation Reflex w/ PDE 5 Inhibitors.
• Phosphodiesterase 5 inhibitors: enhance the effects of NO by inhibiting the enzyme that normally breaks
down cGMP. Decreases cGMP degradation thereby increasing cGMP and increase vasodilation.
Sildenafil, Vardenafil, Tadalafil* *(~ 4x longer duration than others, ~ 16h)
• Prevents degradation of cGMP
• Orally effective
• Metabolized by CYP 3A4
• Headache, flushing, dyspepsia, nasal congestion
• Do not use with nitrates or a-blockers
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Becky Stepan
Rose – Hellenkant – Physiology of Male Puberty