An overview of the role of Gonadotropins (FSH, HMG and HCG) in management of male infertility. Includes a discussion on different treatment protocols.

1. Gonadotropins
Male infertilityin

2. Contents
▷Male infertility
▷Burden and etiology
▷Treatment options
▷HMG & HCG – Role in infertility
▷Protocol – dose and dosage
▷Evidence based medicine
▷Summary and conclusion

3. ““Infertility is the inability of a sexually active, non-
contracepting couple to achieve spontaneous
pregnancy in 1 year”
Male infertility due to impaired spermatogenesis may
result from hypothalamic, pituitary or testicular
disorders.
Male infertility

4. “Subfertility refers to any individual with
compromised or reduced fertility potential.
Includes patients with known endocrine diseases
that could interfere with spermatogenesis and
testicular function or those with abnormalities on
semen analysis
Subfertility

5. Global burden of male
infertility
▷Infertility affects an estimated 15% of couples
globally, amounting to 48.5 million couples.
▷Males are found to be solely responsible for
20-30% of infertility cases and contribute to
50% of cases overall.
▷However, this number does not accurately
represent all regions of the world.
Agarwal et al. Reproductive Biology and Endocrinology (2015) 13:37

6. Indian burden of male
infertility
Male infertility accounts for 40-50% of
infertility, affects 7% of all men
▷Normozoospermia was observed in 35.80%
▷Oligozoospermia in 34.14%
▷Asthenoteratozoospermia in 19.35%
▷Azoospermia in 10.70%
Indian Journal of Obstetrics and Gynaecology Research 2015;2(3):132-136

7. Reasons for a reduction
in male fertility
Congenital factors (cryptorchidism and testicular
dysgenesis, congenital absence of the vas deferens)
Acquired urogenital abnormalities (obstructions,
testicular torsion, testicular tumour, orchitis)
Urogenital tract infections
Increased scrotal temperature (e.g. due to varicocele)
Endocrine disturbances
Genetic abnormalities

8. Reasons for a reduction
in male fertility
Immunological factors (autoimmune diseases, anti-sperm
antibodies)
Systemic diseases (diabetes, renal and liver insufficiency,
cancer, hemochromatosis)
Exogenous factors (medications, toxins, irradiation)
Lifestyle factors (obesity, smoking, drugs, anabolic
steroids)
Idiopathic (40-50% of cases)

9. Diagnostic evaluation of
male infertility
History
Physical examination
Semen analysis
Endocrine & hormonal evaluation

11. Diagnostic evaluation of male
infertility – Hormonal investigation
Categorization of Oligospermic Men by Endocrine Profile
Oligospermia T FSH LH PRL
Eugonadotropic N N N N
Hypergonadotropic
hypogonadism
↓ ↑ ↑ N
Injury to germinal
epithelium
N ↑ N N
Hypogonadotropic
hypogonadism
↓ ↓ ↓ N
Partial androgen
insensitivity
↑ NI ↑ NI
Hyperprolactinemia ↓ ↓ ↓ ↓

12. Hypogonadotropic
hypogonadism (HH)
 is a condition which is characterized by
hypogonadism due to
 an impaired secretion of gonadotropins,
including FSH and LH by the pituitary gland
in the brain
 and in turn decreased gonadotropin levels
and a resultant lack of sex steroid
production.

13. Hypothalamus secretes GnRH
Anterior pituitary secretes FSH & LH
Stimulates sperm production
& secretion of Inhibin B
Inhibin B regulates pitutory FSH
secretion by negative feedback
FSH binds to receptors on sertoli cells
LH stimulates leydig cells to
produce testosterone
Rising androgen levels
have inhibitory effect on
secretion of GnRH,
FSH & LH

14. Hypogonadotropic
hypogonadism (HH)
The type of HH, based on its cause, may be classified as either
primary or secondary.
o Primary HH: caused by congenital syndromes such as
Kallmann syndrome, CHARGE syndrome and GnRH
insensitivity.
o Secondary HH: far more common than primary HH, and is
responsible for most cases of the condition.
▷ Causes include: brain or pituitary tumors, pituitary apoplexy,
head trauma, ingestion of certain drugs and certain systemic
diseases & syndromes.

15. Hypogonadotrophic
hypogonadism (low FSH/LH)
Low levels of gonadotrophins due to dysfunction of the pituitary
gland or hypothalamus are rare and may occur as a result of:
Congenital anomalies: idiopathic Hypogonadotrophic
Hypogonadism (iHH), Kallmann’s syndrome, Prader-Willi syndrome;
Acquired anomalies: acquired hypothalamic/pituitary gland
diseases (malignant CNS tumours, pituitary adenoma,
hyperprolactinaemia, granulomatous illness, hemochromatosis)
Exogenous factors: drugs (anabolic steroids, obesity, irradiation).

16. Medical treatment of
Male infertility
Hormonal treatment
Gonadotropin releasing hormone
Gonadotropins
Dopamine agonist
Aromatase inhibitor therapy
Selective estrogen receptor modulator
Antioxidants

17. Goal of infertility treatment
in HH
 to optimize LH levels to stimulate Testosterone
production from the Leydig cells,
 to optimize FSH levels to stimulate Sertoli cells and
spermatogenesis, and eliminate any estrogen
excess

18. Treatment of HH
Gonadotropins are proven and medically necessary
for the treatment for male hypogonadotropic
hypogonadism for
 One of the following conditions:
Primary hypogonadotropic hypogonadism
(or) secondary hypogonadotropic hypogonadism
 For the induction of spermatogenesis
 And infertility that is NOT due to primary testicular
failure.

19. Role in male infertility
 Secondary hypogonadism is associated with decreased
secretion of the gonadotropins LH and FSH
 Resulting in reductions in testosterone secretion and
sperm production.
 Testosterone secretion virtually always increases to
normal after replacement of LH, and sperm production
more often than not increases after replacement of LH
alone or LH plus FSH
 Gonadotropins are more convenient to administer than
pulsatile gonadotropin-releasing hormone (GnRH)

20. Role in male infertility
The pharmacologic effects of HMG are those of
 FSH: Stimulates sperm production in males
 LH: Causes androgen production in males
HMG administered concomitantly with HCG for at
least 3 months induces spermatogenesis in men
with pituitary hypofunction

21. Treatment of male infertility
 HMG indicated for induction of
spermatogenesis in men with primary or
secondary hypogonadotropic hypogonadism
 in whom the cause of infertility is not due to
primary testicular failure

22. HMG: Dosage and administration
 HMG is administered by IM injection
 Dosage is expressed in terms of IU of FSH
activity and IU of LH activity
 The recommended dose of HMG is 75 IU of
FSH and 75 IU of LH 3 times weekly in
conjunction with 2000 IU HCG 2 times weekly.
This course should be continued for at least 4
months.

23. HMG: Treatment duration
 Normal spermatogenesis takes three months.
 Restoration of a normal sperm count usually
does not occur for at least 3 and sometimes 6
months or more after the serum prolactin and
testosterone concentrations have returned to
normal.

24. Clinical evidence

25. In patients with hypogonadotropic
hypogonadism,
 hCG can be administered in combination
with hMG
 hCG monotherapy is given until normal
serum testosterone levels are achieved.
 Spermatogenesis is observed in 80-90% of
patients on this regimen

26.  treatment with gonadotropins resulted in
conception in 75% and live births in 59% of
the cases
 it seems that in male patients with
hypogonadotropic hypogonadism, this
regimen is the treatment of choice.

27. Group I: GnRH, Group II: hCG/hMG
 In patients of group II, 30 therapy cycles
with hCG/hMG were initiated and all were
successful in induction of spermatogenesis.
 In group II the pregnancy rate per therapy
cycle was 17/ 21 (81%)

28. Effectiveness of therapy in terms of induction
of spermatogenesis and pregnancy rates
1. Left column: GnRH for IHH/KalS
patients.
2. Centre column: hCG/hMG for
IHH/KalS patients.
3. Right column: hCG/hMG for
hypopituitarism patients.

29. A prospective, open-label, 21 men, with a diagnosis of
hypogonadotropic hypogonadism, evaluated the
efficacy of gonadotropin treatment in stimulating
spermatogenesis
 Study participants were initially treated with hCG
2,000 IU thrice weekly
 If the sperm count did not increase, the men were
started on human menopausal gonadotropins hMG
75 IU thrice weekly

30. Results:
 The sperm count increased to within normal
limits in 5 of the 7 men with prepubertal
onset of hypogonadism
 The authors conclude that hMG treatment
will usually increase sperm count to normal
in men with hypogonadotropic
hypogonadism

31. 113 infertile men with varicocele were divided into 4
groups:
A. Group received HCG 5000 IU weekly
B. Group received HMG 75 IU 3 times a week
C. Group received rhFSH 75 IU 3 times a week
D. Group received no medical treatment

32. Sperm morphology before and after treatment with
5000 IU/week HCG, 75 IU HMG 3 times a week
Sperm motility before and after treatment with 5000
IU/week HCG, 75 IU HMG 3 times a week

33. Sperm concentration before and after treatment
with 5000 IU/week HCG, 75 IU HMG 3 times a week

34. Summary & conclusion

35. HMG in male infertility due to
Hypogonadotrophic hypogonadism
HMG is a purified preparation of FSH and LH
obtained from the urine of post-menopausal women
FSH: Stimulates sperm production in males
LH: Causes androgen production in males
Administered by IM injection
Used 3 times weekly in conjunction with 2000 IU
HCG 2 times weekly. This course should be
continued for at least 4 months.