Hypogonadism is characterized by impaired testicular function and can affect sperm production and testosterone synthesis. It has three main categories: primary hypogonadism due to testicular failure, secondary (hypogonadotropic) hypogonadism caused by insufficient gonadotropin secretion, and androgen insensitivity. Hypogonadotropic hypogonadism is rare and can be congenital or acquired. Kallmann syndrome results from GnRH deficiency due to failed embryonic migration and causes anosmia and azoospermia. Prader-Willi syndrome is caused by chromosome abnormalities and results in obesity, short stature, and cryptorchidism. Treatment of hypogonadotropic hyp

1. HYPOGONADOTROPIC
HYPOGONADISM
Eko Indra
Pradono

2. OVERVIEW OF
HYPOGONADISM
Hypogonadism is characterised by impaired testicular function, which
may affect spermatogenesis and/or testosterone synthesis
The symptoms of hypogonadism depend on the degree of androgen
deficiency
The aetiological and pathogenetic mechanisms of male
hypogonadism can be divided into 3 main categories :
Primary (hypergonadotropic)
hypogonadism due to
testicular failure
Secondary
(hypogonadotropic)
hypogonadism caused by
insufficient GnRH and/or
gonadotropin (FSH, LH)
secretion
Androgen insensitivity (end-
organ resistance

3. OVERVIEW
Isolated gonadotropin deficiency or hypogonadotropic hypogonadism (HH)
•Rare cause of subfertility (1% of male infertility cases)
•Congenital or acquired
Acquired causes :
Pituitary disease (prior surgery, infarction, tumors, infection, metabolic
conditions)
Most common  anosmic form or Kallman syndrome (1:10,000 and
1:60,000 births)

5. KALLMAN SYNDROME (1)
Results from failure to secrete GnRH by the
hypothalamus  low gonadotropin levels  failure to
transition prepubertal testis to postpubertal level of
function
GnRH deficiency  result of failed embryonic migration
of neuroendocrine GnRH cells from olfactory epithelium
to forebrain
 Absence or hypoplasia of olfactory bulbs  concurrent
anosmia
Kallman syndrome represents genetically diverse group
of diseases with:
 Both X-chromosome linked inheritance via mutation in
KAL1 gene
 Autosomal dominant inheritance via mutations in
Fibroblast Growt Factor Reseptor 1 (FGFR1), FGFR8,

6. KALLMAN SYNDROME (2)
Clinical features:
Anosmia Azoospermia
Midline facial defects
(cleft palate)
Gynecomastia Unilateral renal agenesis
Cryptorchidism Micropenis Pes cavus
Neurologic
abnormalities
•Metal retardation, oculomotor
defects, deafness, synkinesia

7. KALLMAN SYNDROME (3)

8. PRADER-WILLI SYNDROME (1)
• Caused by microdeletions or mutations on the paternal chromosome 15 at the
q11 or 13 location
• Because of concurrent medical problems in these patients, most do not seek
treatment for infertility
• Clinical features :
Infantile
hypotonia
Obesity Cryptorchidism Short stature
Mental
retardation

9. PRADER-WILLI SYNDROME
(2)

10. DIAGNOSTIC OF HH (1)
HH usually presents in the late teenage years when the patient fails to undergo the
usual pubertal changes with secondary virilization
Important to distinguish HH from constitutional delay of growth and puberty (CGDP)
because they share many clinical and hormonal features and yet require markedly
different treatments
HH
• Require lifelong androgen replacement
for maintenance of virilization and
episodes of exogenous gonadotropin
treatment off androgen therapy for
fertility induction
CGDP
• Attain spontaneous puberty by age 18
• May require transient androgen
replacement for puberty induction but
then will progress through normal
development and fertility

11. DIAGNOSTIC OF HH (2)
Number of physiologic and stimulatory tests to discriminate :
 Serial serum LH measurements
 Prolactin response to THR and GnRH
 HCG stimulation tests
HH
• Have minimal variability in LH
levels
• Do not demonstrate significant
increases in gonadotropins levels
with administration of GnRH
CGDP
• Often demonstrate LH pulses with
serial overnight blood draws
• Gonadotropin surge in response
to GnRH stimulation

12. DIAGNOSTIC OF HH (3)
A suspected tumour requires imaging [computed tomography (CT) or
magnetic resonance imaging (MRI)] of the sella region and a complete
endocrine work-up
Normal androgen levels and subsequent development of secondary
sex characteristics (in cases of onset of hypogonadism before
puberty) and a eugonadal state can be achieved by androgen
replacement alone

13. GOALS OF HH TREATMENT
Induction of normal serum androgen levels to allow
appropriate virilization and bone growth
induction of spermatogenesis and fertility

14. TREATMENTS OF HH (1)
Various effective methods of testosterone replacement therapy
Intramuscular
testosterone
enanthate or
cypionate
(200mg every 2
weeks)
Transdermal
patches (5-
10mg/day)
Testosterone
gel
Buccal tablets
Adequacy of replacement can be assessed by:
 Serum testosterone levels (within midrange of normal)
 Observation of desired phenotypic response to therapy

15. EAU RECOMMENDATIONS
Recommendations Strength rating
Provide testosterone replacement therapy for symptomatic patients with primary and secondary
hypogonadism who are not considering parenthood.
Strong
In men with hypogonadotropic hypogonadism, induce spermatogenesis by an effective drug
therapy (human chorionic gonadotropin, human menopausal gonadotropins, recombinant
follicle-stimulating hormone, highly purified FSH).
Strong
Do not use testosterone replacement for the treatment of male infertility. Strong

16. TREATMENTS OF HH (1)
 human Chorionic Gonadotropin (hCG) as First-line therapy :
subcutaneously at a dose of 1500 to 2000 IU two to three times
per week, for 4 to 6 months.
 Without significant further improvement, FSH stimulation is added
to the treatment regimen to induce spermatogenesis

17. TREATMENTS OF HH (2)
FSH (administed as human menopausal gonadotropin/hMG)
 Contains both FSH & LH in equal dose or with recombinant human FSH
formulation
 at a dose of 75 IU, 2-3x/week and recombinant FSH at a dose of 37.5-75 IU, 2-
3x/weeks
 continued until attainment of sperm concentrations of at least 5 million per mL in
the ejaculate or pregnancy
Clomiphene (antiestrogen) or tamoxifen or with aromatase inhibitors such as
anastrozole or letrozole
restore testosterone levels and possibly improve spermatogenesis in selected
patients with HH presenting after puberty with intact pituitary function
 initial dose 25 mg every day or 50 mg every other day and is increased by

18. TREATMENTS OF HH (3)
In some studies, the titration target is restoration of normal
androgen levels; in others, it is elevated at 600 to 800 ng/dL
The typical dose of anastrozole is 1 mg daily

19. TREATMENT OUTCOME &
CONSIDERATIONS
 The vast majority of patients will be able to conceive after
gonadotropin therapy, although 71% of the patients with
subsequent fertility have sperm concentrations considerably lower
than normal, suggesting that these patients are often able to
conceive with low counts
 10% of patients may maintain normal serum testosterone levels
after cessation of all endocrine therapy, implying that HH may be
reversible in some patients
 In patients who have developed hypogonadism before puberty and
have not been treated with gonadotropins or GnRH  may be need
one to two years of therapy to achieve sperm production

20. HH MEDICATIONS
Menopur : Menotropin/human Menopausal Gonadotropin (hMG) 225
IU FSH & 225 IU LH
@75 IU, SC 2-3x/week, until attainment of sperm concentration (at
least 5 million/ml) or pegnancy is obtained
 Roburantia Starfer/Torrex :
Zink, Folic Acid, Ascorbic acid, cyanocobalamin, sodium selenium,
fructose, arginine, carnitine, Vit E

21. REFERENCES
Jungwirth A, Diemer T, Kopa Z, Krausz C, Minhas S, Tournaye H. Male
infertility. EAU Guidelines 2019.
Niederberger CS. Chapter 24: Male infertility. In: Kavoussi LR, Partin
AW, Peters CA. Campbell-walsh Urology. 11th ed. Philadelphia:
Elsevier, Inc.;2016.

24. DISORDER
ASSOCIATED W/ MALE
HYPOGONADISM