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1. Endocrinological aspect of
Male infertility
Done by Dr. Yahya Hamzawi

2. Definition of male infertility
• A man is not able to start a pregnancy with his
female partner

3. HYPOTHALAMIC-PITUITARY-GONADAL AXIS
• The HPG axis plays a critical role during development and
adulthood in four physiologic processes:-
(1) phenotypic gender development during embryogenesis,
(2) sexual maturation at puberty,
(3) testis endocrine function—testosterone production, and
(4) testis exocrine function—sperm production

8. Hypothalamus
• The pulse generator for the cyclic secretion of pituitary hormones,
the hypothalamus is anatomically linked to the pituitary gland by
a portal vascular system and neuronal pathways.
• By avoiding the systemic circulation, the portal vascular system
allows direct delivery of hypothalamic hormones to the anterior
pituitary.

9. Hypothalamus
• The most important hypothalamic hormone for reproduction is
gonadotropin-releasing hormone (GnRH), a 10–amino acid peptide
generated in the neuronal cell bodies in the preoptic and arcuate
nuclei. Currently, the only known function of GnRH is to stimulate
the secretion of LH and FSH from the anterior pituitary.

10. Hypothalamus
• GnRH output exhibits several types of rhythmicity: seasonal, on a
time scale of months and peaking in the spring; circadian,
resulting in higher testosterone levels during the early morning
hours; and pulsatile, with GnRH peaks occurring every 90 to 120
minutes on average.
• The importance of pulsatile GnRH secretions in normal HPG axis
function is aptly demonstrated by the ability of exogenous GnRH
agonists (e.g., leuprolide acetate) to stop testicular testosterone
production by changing pituitary exposure to GnRH from a cyclic
to a constant pattern

11. Anterior Pituitary
• The anterior pituitary, or adenohypophysis, is regulated by blood-
borne factors and is the site of action of GnRH.
• LH and FSH are the primary pituitary hormones that regulate testis
function and only known to act in the gonads.

12. Anterior Pituitary
• Secretory pulses of LH vary in frequency from 8 to 16 pulses in 24
hours and vary in amplitude by onefold to threefold and these
pulse patterns closely reflect GnRH release.
• Androgens and estrogens regulate LH secretion through negative
feedback.
• On average, FSH pulses occur every 1.5 hours and vary in
amplitude by 25%.

13. Anterior Pituitary
The FSH response to GnRH is more difficult to assess than that of LH
for two reasons:-
(1) FSH has a smaller amplitude response and a longer serum half-
life and
(2) the gonadal proteins inhibin and activin may affect FSH
secretion and are thought to account for the relative secretory
independence of FSH from GnRH secretion.

14. Anterior Pituitary
• In the testis, LH stimulates steroidogenesis within Leydig cells by
inducing the mitochondrial conversion of cholesterol to
pregnenolone and testosterone.
• FSH binds to Sertoli cells and spermatogonial membranes within
the testis and is the major stimulator of seminiferous tubule
growth during development.
• FSH is essential for the initiation of spermatogenesis at puberty. In
the adult, the major physiologic role of FSH is to stimulate
quantitatively normal levels of spermatogenesis

15. Testis
• Normal male virility and fertility require the collaboration of the
exocrine and endocrine testis.
• The interstitial compartment, composed mainly of Leydig cells, is
responsible for steroidogenesis.
• The seminiferous tubules produce spermatozoa.

16. Testis
• Normal testosterone production in men is approximately 5 g/ day,
and secretion occurs in a damped, irregular, pulsatile manner
(nyctohemeral).
• Testosterone is metabolized into two major active metabolites in
target tissue: (1) the major androgen dihydrotestosterone (DHT)
from the action of 5α-reductase, and (2) the estrogen estradiol
through the action of aromatases.
• DHT is a much more potent androgen than is testosterone.

17. Testis
• In most peripheral target tissues, testosterone reduction to DHT is
required for androgen action, but in the testis and skeletal
muscle, conversion to DHT is not essential for hormonal activity.
• The primary site of FSH action is on Sertoli cells within
seminiferous tubules.

18. Testis
• The testis also produces the protein hormones inhibin and activin.
• Inhibin is a 32-kD protein made by Sertoli cells that inhibits FSH
release from the pituitary. Within the testis, inhibin production is
stimulated by FSH and acts by negative feedback at the pituitary
or hypothalamus.
• Activin, a testis protein with close structural homology to
transforming growth factor-β (TGF-β), exerts a stimulatory effect
on FSH secretion.

19. Testis
• Negative feedback suppression of GnRH release by testosterone
occurs through androgen receptors (ARs) in hypothalamic neurons
and in the pituitary.
• Testosterone feedback occurs mainly at the hypothalamus,
whereas estrogen feedback is mainly in the pituitary.
• It also appears that although testosterone is the primary regulator
of LH secretion,
• Estradiol (along with inhibin from Sertoli cells) is the predominant
regulator of FSH secretion.

20. Cause of Hypogonadotropic Hypogonadism
• Damage to the pituitary gland or hypothalamus from surgery, injury,
tumor, infection, or radiation
• Genetic defects ( Kallmann syndrome is an inherited form of HH. Some people
with this condition also have anosmia (loss of the sense of smell).
• High doses or long-term use of opioid or steroid (glucocorticoid)
medicines
• High prolactin level (a hormone released by the pituitary)
• Severe stress
• Nutritional problems (both rapid weight gain or weight loss)

21. Cause of Hypogonadotropic Hypogonadism
• Long-term (chronic) medical diseases, including chronic
inflammation or infections ( type 2 DM, sarcoidosis )
• Drug use, such as heroin or use or abuse of prescription opiate
medicines
• Certain medical conditions, such as iron overload

22. Diagnosis
Laboratory investigations
• Seminal fluid analysis
• S. Testosterone
• S. Estradiol
• FSH, LH
• TFT
• S. Prolactin
• Genetic studies

24. Treatment
• Treatment includes replacement of LH with human
chorionic gonadotropin (hCG) and replacement of FSH
with recombinant FSH (rFSH) or hMG, which exhibits LH-
and FSH-like activity.

25. Treatment
• Typical doses for intramuscular or subcutaneous hCG are
1500 to 5000 IU two to three times weekly to a maximum
of 10,000 IU/wk and are titrated to serum testosterone
results.
• The dose of hMG is 75 IU two to three times weekly,
typically administered subcutaneously.

29. Treatment
• Isolated LH deficiency found to have adequate spermatogenesis
but hypoandrogenism.
• Isolated FSH deficiency found to have adequate androgenization
but impaired spermatogenesis.
• Treatment includes GnRH administration by a subcutaneous
portable mini-infusion pump every 2 hours, and, as with treatment
for Kallmann syndrome, longterm courses of at least 6 months’
duration may be required.

30. Treatment
• Incomplete forms with hypoandrogenism associated with serum LH
concentrations above those observed with Kallmann syndrome but
lower than expected for the diminished testosterone are common.
• For these men, pituitary stimulation with antiestrogenic agents
such as clomiphene or tamoxifen or with aromatase inhibitors such
as anastrozole or letrozole may restore testosterone levels and
possibly improve spermatogenesis

31. Treatment
• Clomiphene citrate is a selective estrogen receptor modulator that
is currently FDA approved for women. It has been used as an off-
label treatment for male hypogonadism and infertility for more
than 40 years, and it is proven to significantly increase
testosterone levels without changes in PSA or hematocrit levels.

33. Treatment
• The initial dose of clomiphene citrate is typically 25 mg every day
or 50 mg every other day and is increased by titrating to serum
testosterone to a maximum of 100 mg daily.
• In some studies, the titration target is restoration of normal
androgen levels; in others, it is elevated at 600 to 800 ng/dL