Page 153 - Remedial Andrology

testosterone release in men with failure of their hypothalamic-pituitary-gonadal axis. Human Chorionic
Gonadotrophin can adequately stimulate spermatogenesis in men whom have developed hypopituitarism after
normal puberty. Therefore, the treatment of men with secondary hypogonadism depends on whether or not
they developed hypothalamic-pituitary failure before or after puberty [5].

10.5.3.2 Secondary hypogonadism
10.5.3.2.1 Pre-Pubertal-Onset
Congenital causes resulting in low gonadotropin production are associated with testicular size < 4 mL and/or
cryptorchidism. Testes size of < 4 mL occurs when they have not been exposed to any gonadotropins at all.
These conditions require combination therapy with both hCG and FSH with subcutaneous administration or
GnRH by pulsed delivery using a subcutaneous pump [1806]. However, GnRH treatment requires a pulsatile
secretion using specific devices for either intravenous or subcutaneous administration, which may limit patient
compliance. Moreover, GnRH therapy should be limited to subjects with a residual pituitary gonadotropic
activity [5].

As for the type of gonadotropin treatment, it is usual to commence hCG first and titrate the dose to achieve
testosterone levels within the normal physiological range. However, FSH can be given first or in combination
with hCG [110]. Human Chorionic Gonadotrophin is given twice weekly and in patients with congenital
secondary hypogonadism in high dose, commencing at 1,000 IU twice weekly. Testosterone levels can be
assayed every 2 weeks with dose increases until ideally mid-range testosterone is achieved. Dose increases
can be to 2,000, 3,000, 4,000 and 5,000 IU two or three times a week, until normal testosterone levels are
achieved [1807-1810]. Failure to achieve normal testosterone status at the high dose would indicate that
primary testicular failure is present; probably as a result of cryptorchidism or failure of testicular development.
Human Chorionic Gonadotrophin is also used to stimulate testicular descent into the scrotum in individuals
with cryptorchidism. Once the hCG dose giving a normal level testosterone is established with the implication
that intra-testicular testosterone has occurred, FSH 75-150 IU three times per week subcutaneously should
be commenced. Usually the higher 150 IU dose three times weekly is needed to be successful in men
with testicular volume < 4mL. The trophic response of the testes to FSH is variable in these patients and it
may range from no effect to achieving testicular sizes of 12-15 mL [1811]. A trophic response is usually an
indication of an increase in spermatogenesis. The production of new spermatogenesis may be evident after
3 months of FSH therapy, but could occur even after 18 months of treatment [1809-1811]. A low baseline
sperm concentration does not indicate a poor response to gonadotropin therapy [1812]. Semen analysis
can be assessed at 3-monthly intervals. These patients can be fertile with low sperm counts < 20 million/
mL as there is a high proportion of motile sperm. Follicle-stimulating hormone therapy prior to GnRH is also
effective in stimulating testicular growth and fertility in men with congenital hypogonadotropic hypogonadism
(HH) [1813]. A larger initial testicular volume is the best prognostic factor for induction of successful
spermatogenesis [1814].

10.5.3.2.2 Post-Pubertal Onset Secondary
If secondary hypogonadism develops after puberty, hCG alone is usually required first to stimulate
spermatogenesis. Doses of subcutaneous hCG required may be lower than those used in individuals with
pre-pubertal onset; therefore, a starting dose of 250 IU twice weekly is suggested, and if normal testosterone
levels are reached, hCG doses may be increased up to 2,000 IU twice weekly as for pre-pubertal onset. Again,
semen analysis should be performed every 3 months to assess response, unless conception has taken place.
If there is a failure of stimulation of spermatogenesis, then FSH can be added (75 IU three times per week,
increasing to 150 IU three times per week if indicated). Similarly, combination therapy with FSH and hCG
can be administered from the beginning of treatment, promoting better outcomes in men with HH [110]. No
difference in outcomes were observed when urinary-derived, highly purified FSH was compared to recombinant
FSH [110].

Greater baseline testicular volume is a good prognostic indicator for response to gonadotrophin treatment
[1814]. Data had suggested that previous testosterone therapy can have a negative impact on gonadotropin
treatment outcomes in men with HH [1814]. However, this observation has been subsequently refuted by a
meta-analysis that did not confirm a real negative role of testosterone therapy in terms of future fertility in this
specific setting [110].

In the presence of hyperprolactinaemia, causing suppression of gonadotrophins resulting in sub-fertility the
treatment independent of aetiology (including a pituitary adenoma) is dopamine agonist therapy or withdrawal
of the drug that causes the condition. Dopamine agonists used include bromocriptine, cabergoline and
quinagolide.

152 SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021