Management of Male Hypogonadotrophic Hypogonadism

14 Pages·2007·0.22 MB·English

Endocrine Journal 2007, 54 (2), 177–190
REVIEW
Management of Male Hypogonadotrophic Hypogonadism
COLIN M HOWLES, TOSHIAKI TANAKA* AND TADASHI MATSUDA**
Department of Global Product Development, Merck Serono International SA, Geneva, Switzerland
*Department of Clinical Laboratory Medicine, National Center For Child Health and Development, Ohkura, Setagaya-ku, Tokyo,
Japan
**Department of Urology and Andrology, Kansai Medical University, Shinmachi, Hirakata, Osaka, Japan
Key words: Male, Hypogonadism, Spermatogenesis, hCG, r-hFSH, Testosterone
(Endocrine Journal 54: 177–190, 2007)
THE development of sexual maturity and reproductive quently for the initiation and maintenance of male
function in the male is dependent upon appropriate se- reproductive function and spermatogenesis. Feedback
cretion of hormones that orchestrate the sophisticated mechanisms play an important role in maintaining the
relationship between the hypothalamus, pituitary, and reproductive axis: testosterone inhibits LH secretion,
testes — the hypothalamic-pituitary-gonadal (HPG) and inhibin secreted by Sertoli cells regulates FSH
axis. A state of hypogonadism, i.e. inadequate testicu- secretion. A reduction in negative feedback results in
lar function, is manifested by deficiencies in secretion an increased secretion of FSH, and, in a manner simi-
of androgens, with a wide range of effects on a number lar to that found in the female with diminished ovarian
of physiological processes, including gametogenesis. function, serum FSH levels in the male act as an indi-
Any dysfunction in the HPG axis can result in hypo- cator of germinal epithelial function in the testis [2, 3].
gonadotrophic hypogonadism, where a decrease in Episodic secretion of GnRH is an essential part of
endocrine and/or gametogenic function of the testes this process. The hypothalamic pituitary gonadal axis
results in retardation of puberty and reproductive in- is first activated during the fetal/neonatal period, when
sufficiency [1]. an increase in testosterone stimulates completion of
The hypothalamus is the centre of the reproductive the inguinoscrotal phase of testicular descent and fur-
axis. Messages received from the central nervous sys- ther growth of the penis. This is accompanied by a
tem and from the gonads are integrated by the hypo- wave of Sertoli and germ cell proliferation in the testis.
thalamus to regulate the production and secretion of A second wave of increased HPG axis activity then oc-
gonadotrophin releasing hormone (GnRH), which is curs during the early stages of puberty, with a second
released in a pulsatile manner that is essential for stim- wave of Sertoli cell proliferation. This wave of pro-
ulating the production and release of follicle stimulat- liferation is followed by terminal differentiation, and
ing hormone (FSH) and luteinizing hormone (LH) Leydig cells begin to secrete testosterone, allowing the
from the pituitary. The anterior pituitary produces LH normal development of puberty [4].
and FSH in response to pulses of GnRH stimulation, A disruption in any of these events, from fetal to
and in the male LH and FSH both bind to specific adult life, can lead to hypogonadism, and this can be
receptors on the Leydig and Sertoli cells within the manifested in a wide variety of clinical symptoms,
testis. This stimulation regulates the release of andro- according to the time of onset and the severity of the
gens required for pubertal development, and subse- resulting hormone deficiency. In many cases, the
symptoms may not be recognised before puberty. Hy-
pogonadism can be classified into three categories,
Correspondence to: Dr. Colin M HOWLES, Merck Serono
International SA, Department of Global Product Development, 9 which must be considered in establishing the diagnosis
Chemin des Mines, Case Postale 54, Geneva, 1211, Switzerland required for correct management and treatment:
178 HOWLES et al.
1.Primary: congenital Leydig cell aplasia or damage Diagnosis
to Leydig cells impairs testosterone secretion and/or
damages the seminiferous tubules, with consequent History and examination
oligospermia and elevated FSH and LH (hyper-
gonadotrophic hypogonadism). Klinefelter’s syn- The background physiology behind male hypo-
drome is the most common cause of primary gonadotrophic hypogonadism clearly indicates that the
hypogonadism, where the 47XXY karyotype is history and symptoms of the condition will depend
associated with seminiferous tubule dysgenesis [5]. on the patient’s age at the time of onset, and therefore
Testicular trauma, surgery, mumps, toxins, radiation it is essential to establish the diagnosis, define the
and chemotherapy can also cause testicular failure aetiology, and identify any associated features in order
with hypergonadotrophic hypogonadism. to manage the patient appropriately [8]. A complete
2.Disorders of the hypothalamus or pituitary impair medical and family history, in combination with phys-
gonadotrophin secretion (hypogonadotrophic hypo- ical examination will help to define whether the aetiol-
gonadism, HH). The primary feature of HH is a ogy is based upon the hypothalamus or pituitary, and
failure in the HPG feedback system, in that low tes- whether the defect is structural, functional, infiltrative
tosterone levels fail to elicit a reciprocal increase in or inflammatory, and congenital or acquired. Relevant
gonadotrophins. features include state of external genitalia such as
3.Androgen resistance: a defect in the androgen recep- small testes or micropenis, a history of cryptorchidism
tor gene causes an inadequate response to available or migrating testes, renal abnormalities, visual field
androgens, resulting in a variety of phenotypic man- defects, cleft lip, anosmia or hyposmia, and a history
ifestations. of chronic illness or trauma. The patient’s growth pat-
tern can help to distinguish between IHH and delayed
The aetiology of hypogonadotrophic hypogonadism development, and bone age measurements are helpful
may be primary/idiopathic, genetic/congenital or sec- in determining appropriate treatment for the younger
ondary, with resulting primary or secondary testicular age group.
failure. Primary hypogonadism selectively affects the In childhood, androgen deficiency has few conse-
secretion or function of GnRH, and may be due to a quences and may not be recognised, unless it is asso-
variety of different defects. A few genetic causes have ciated with growth retardation or other anatomic or
been identified, such as Kallman’s Syndrome, DAX-1 endocrine abnormalities [9]. Boys with congenital
gene mutation and GPR54 gene mutation, but many hypogonadotropic hypogonadism usually show normal
have not been clearly defined; autosomal dominant, growth, but sometimes manifest micropenis or crypt-
autosomal recessive and sex-linked inheritance have orchidism before pubertal age. Secondary sexual de-
been proposed. In Kallman’s syndrome there is con- velopment is impaired if it occurs at the expected time
genital agenesis of the olfactory lobes, so that fetal of puberty. Males who do not produce sufficient tes-
GnRH neurosecretory neurons fail to migrate from the tosterone at the appropriate adolescent age may expe-
olfactory placode to the hypothalamus [5]. Secondary rience behavioural and cognitive impairment. Patients
HH and testicular failure can be due to congenital or at late adolescent have poor muscle development, small
acquired pathology at the level of the hypothalamus or testes, phallus and prostate, scant pubic and axillary
pituitary, including tumors, neoplastic therapy, vascu- hair, long arms and legs due to delayed epiphyseal
lar disorders, sarcoid, infections, trauma, AIDS [6], closure, gynecomastia, and a high-pitched voice. A
malnutrition, or the stress of acute illness such as boy who has no pubertal development by the age of 14
chronic renal insufficiency or anorexia nervosa [6, 7]. may have constitutional delay of puberty, and there is
In some cases, the aetiology is unknown, and males often a family history of delay in sexual development
with isolated/idiopathic HH may present either with in a parent or sibling. These boys usually have short
constitutional delay of puberty, or later, with infertility stature during childhood and/or adolescence, with a
as the primary feature. growth pattern that parallels the lower percentile
groups of the growth chart. When the bone age is
plotted on the growth curve, it essentially equals the
percentile group of the genetic target; the majority will
DIAGNOSIS AND TREATMENT OF MALE HYPOGONADOTROPHIC HYPOGONADISM 179
Table 1. Summary of findings, potential diagnoses and recommended strategies in adult males with hypogonadism (adapted from
AACE Guidelines 2002) (10)
Testicular size FSH LH Testosterone Semen Analysis Diagnosis Evaluation or treatment
Not palpable High High Low Azoospermia Anarchism Surgical exploration
Not palpable High High N or low Azoospermia Bilat cryptorchidism Surgical exploration
<5ml Low Low Low Oligo/azoospermia Kallman’s syndrome, T for virilization, hCG/
hypogondadotropic FSH for spermatogenesis
hypogonadism
<5ml High High N or Low Azoospermia Klinefelter’s, other Karyotype to confirm, T
hypergonadotrophic for virilization
syndromes
8–15ml High N N Azoo/oligospermia Germinal damage, toxins, Fertility: IVF with ICSI
idiopathic
10–20ml Low Low Low Oligospermia Adult acquired hypo hypo Pituitary MRI, prolactin;
treat pituitary disorder if
present, otherwise treat
as Kallman’s
10–20ml N or high N or high N or low Variable Senescence T if symptomatic with
low T
15–20ml N or high N N Oligospermia Varicocele, drugs, Fertility: varicocele
idiopathic repair if significant, IVF
with ICSI
Variable phenotype High High High Variable T receptor defects, Variable, depending on
Reifenstein’s Syndrome degree; medical or
surgical therapy
20–30ml N N N Azoospermia Obstruction Fertility: surgical repair
or surgical sperm
aspiration, ICSI
have evidence of sexual maturation by the age of volume (TV) may therefore be used as an indicator of
18yrs and ultimately reach their genetic target for probable time of onset of the disorder: prepubertal
height. Other pathology must be excluded, i.e., growth testes are smaller than 4ml in volume and <2cm in
hormone deficiency, hypothyroidism, primary or sec- length, testes at the early puberty are 4–15ml and
ondary hypogonadism — before a diagnosis of con- >2cm long, and adult testes are usually between 20–
stitutional delay is reached. 30ml, and 4.5 to 6.5cm long by 2.8 to 3.3cm wide
In an adult, the androgen deficiency of hypo- [11, 12]. Kumar et al. [13] studied testicular biopsies
gonadism may produce clinical symptoms and signs of 8 adult IHH patients with prepubertal testes (<4ml),
that are often subtle and slow to fully evolve — they with no previous gonadotropin therapy and with no
may be denied by the patient, and ignored by the phy- history of cryptorchidism. The testes of all patients
sician. Manifestations depend upon the degree and showed seminiferous cords separated by interstitium
length of deficiency, and include a progressive de- composed of blood vessels, connective tissue cells and
crease in muscle mass, loss of libido, impotence, oligo- collagen fibres but typical adult Leydig cells were ab-
spermia/azoospermia, hot flushes, and poor ability to sent. The cords contained only Sertoli cells and early
concentrate. With long-standing hypogonadism, testic- type A spermatogonia.
ular atrophy, fine wrinkling of the skin around the eyes In boys with delayed puberty, a full endocrine as-
and lips and sparse body hair may been seen [10]. sessment must be carried out in order to identify any
associated deficits in growth hormone, thyroid and
Investigations adrenal function, or possible medical complications
of chronic systemic disorders and treatment. Hyper-
Approximately 85% of testicular mass consists of prolactinaemia, due to a prolactinoma or as a side
germinal tissue, and reduced germinal cell mass is effect of certain medications can also cause HH. A
reflected by small, smooth and soft testes. Testicular small TV may also be due to androgen resistance,
180 HOWLES et al.
where defects in the androgen receptor gene prevent an should be carried out in order to investigate the pos-
adequate response to normal secretion of androgens, sibility of a pituitary tumour. Thyroid, adrenal and
resulting in a variety of phenotypic variations accord- growth hormone tests are also indicated.
ing to the nature of the genetic defect. Children of short stature with delayed pubertal de-
In isolated LH deficiency, patients have a mono- velopment show low testosterone and low gonado-
tropic loss of LH, while FSH remains normal. At pu- trophins — this may be a feature of constitutional
berty, these boys have testicular growth, since the delay as well as HH.
bulk of the testis is made up of seminiferous tubules In the prepubertal period, it may be difficult to
that respond to FSH. However, the absence of LH differentiate between HH and constitutional delay of
causes Leydig cell atrophy and testosterone deficien- puberty, and endocrine challenge tests using either
cy; the patients do not develop secondary sexual char- hCG or GnRH can be useful in determining the
acteristics, and continue to grow because of lack of aetiology of the syndrome [15, 16]. The GnRH test
epiphyseal closure. measures pituitary function: a bolus of 100µg GnRH
An initial blood test should include testosterone, given by rapid IV injection directly stimulates the pi-
prolactin, FSH and LH levels. Testosterone and LH tuitary to release LH and FSH, which are measured
levels vary in a diurnal pattern, and from the second in serum every 20–30minutes for 2hrs. In childhood,
half of puberty are higher at night than during the the response is predominantly an increase in FSH with
day; blood is generally drawn in the morning, when little or no increase in LH. During puberty, LH and
the levels are highest [14]. Testosterone levels in- FSH rise more or less equally by two to threefold. In
crease throughout puberty from <0.7nmol/L to between adulthood, LH rises two to fivefold over baseline,
10.5 and 41.5nm/L or from <10ng/dL to between while FSH rises between 20–50%. If the patient has
250 and 1100ng/dL, and its secretion is pulsatile as pituitary insufficiency (hypopituitarism), this test elic-
well as circadian. its an inadequate to absent increase in gonadotrophins.
Testosterone circulates bound to carrier proteins in Patients with hypothalamic disease may have a normal
the blood, sex-hormone binding globulin (SHBG) and or very low rise in FSH and LH; an inadequate rise
albumin, and any alteration in these protein levels will may be due to atrophy of gonadotrophin-secreting
alter total testosterone measurements. Low testoster- neurons in the pituitary as a result of insufficient endo-
one levels stimulate an increase in SHBG by the liver. genous stimulation by GnRH. In patients with hypo-
In young adult men, approximately 2% of testosterone thalamic disease, such as Kallmann’s syndrome, the
is in the free form, 30% is bound tightly to SHBG, and repeated pulsatile administration of GnRH may restore
68% is weakly bound to albumin [5]. gonadotroph secretion to normal.
LH and FSH are normally secreted in pulses of 90- With the advent of highly purified recombinant
to 120-minute intervals, and therefore these hormones proteins and improved assay techniques it has been
should be measured in nocturnal blood samples at 20- possible to accurately measure mullerian inhibiting
minute intervals for 2hours to document the presence substance (MIS) and inhibin B levels in various patient
or absence of the normal pulses. Serum LH is usually populations including male hypogonadotrophic hypo-
<0.5IU/L and FSH <1IU/L in boys and <3.5IU/L in gonadism [17–19]. Pitteloud et al. [19] compared
girls before puberty, are higher at night in the latter IHH patients according to the absence or presence of
half of puberty, and have a pulsatile fluctuation be- some prior pubertal development and found significant
tween 5 and 20IU/L in adults. differences in inhibin B, and MIS levels. IHH patients
In adult males, low serum testosterone and elevated with a history of some prior pubertal development had
FSH and LH suggest a failure of germinal epithelium significantly lower MIS and significantly higher In-
in the seminiferous tubules, i.e. primary testicular fail- hibin B levels than those individuals with no prior
ure (hypergonadotrophic hypogonadism), whereas low pubertal development.
testosterone and low or normal gonadotrophins sug- Men who have idiopathic seminiferous tubule fail-
gest a hypothalamic or pituitary disorder. A semen ure, or secondary failure due to disease or disorders
analysis provides an excellent index of seminiferous affecting the testes (infection, trauma, cryptorchidism,
tubule function in adolescents or adults. In acquired chemotherapy/radiotherapy, vascular damage, alcohol-
HH, a prolactin level and pituitary imaging studies ism) may have oligo- or azoospermia associated with
DIAGNOSIS AND TREATMENT OF MALE HYPOGONADOTROPHIC HYPOGONADISM 181
infertility, with FSH levels that may be elevated or or hCG and a preparation containing FSH.
normal. Serum testosterone and LH are usually nor- Pulsatile GnRH treatment can be delivered subcuta-
mal, but the GnRH stimulation test may cause an neously through a portable infusion pump if there is
excessive rise in LH [20]. sufficient gonadotroph reserve in the pituitary [8, 23–
Human chorionic gonadotrophin (hCG) has a struc- 25]. LH, FSH and testosterone levels must be moni-
tural subunit that is also common to LH, and therefore tored every two weeks until they reach a normal range,
hCG stimulates Leydig cells to produce testosterone. after which they can be monitored every 2months.
The hCG test is a useful indicator of testicular func- GnRH can be used to initiate pubertal development,
tion. A single dose of hCG, 5000IU/1.7m2 in adults, maintain virilization and sexual function, and to ini-
or 3000IU/m2 in children, should induce at least a tiate and maintain spermatogenesis. In most patients,
doubling in testosterone levels within 3 to 4 days if these effects may take from 3 to 15months to achieve
Leydig cells are functional [16, 21]. sperm production [26]. However, a small subset of
Clomiphene citrate (CC) is a weak oestrogen ago- IHH men, fail to reach a normal testicular volume
nist that interrupts the negative feedback loop and (TV) and produce sperm on this therapy. To deter-
thereby stimulates release of gonadotrophins from mine predictors of outcome in terms of TV and sperm
the pituitary. In the CC challenge test, 100mg of count, Pitteloud et al. [18] studied 76 IHH men (38%
CC is given orally for 5–7days; if the hypothalamic- with anosmia) undergoing GnRH therapy for 12–
pituitary axis is intact, LH levels should double, and 24months. In patients who had complete prior
an FSH rise of between 20–50% is expected [22]. pubertal development (and there was no evidence of
The sensitivity of standard RIA endocrine assays cryptorchidism), response to therapy was faster, nor-
previously limited the value of these challenge tests malizing androgen production by 2months and
[15], particularly in prepubertal boys; however, more completing spermatogenesis by 6 months. The inde-
sensitive assays (IRMA, immunoradiometric assays, pendent predictors of outcome of long-term GnRH
and TR-FIA, time-resolved fluoroimmunoassay) have therapy were: 1) the presence of some prior pubertal
increased the discriminative power of GnRH and hCG development (positive predictor) 2) a baseline Inhibin
testing and improved their diagnostic accuracy [16]. B less than 60pg/ml (negative predictor); and 3) prior
In suspected patients aged 10years and older, a com- cryptorchidism (negative predictor). Notably, anosmia
bination of GnRH and hCG testing provide excellent was not an independent predictor of outcome when
diagnostic value. adjusted for other baseline variables.
The use of an infusion pump for GnRH delivery is
however generally both inconvenient and difficult to
Management maintain for long periods, and the treatment often fails
due to pituitary hypoplasia or downregulation of go-
Gonadotrophin or GnRH therapy to induce or re- nadotrophin receptors. In one study using the GnRH
store secondary sexual development and fertility due pump, Pitteloud et al. [18] reported an 8% (6/76)
to androgen deficiency is effective only in hypogonad- non-compliance rate. Treatment with injectable go-
otrophic hypogonadism, and therefore this diagnosis nadotrophins (hCG with or without FSH) is now more
must be firmly established before treatment is consid- commonly used to treat HH [27]. Several studies have
ered. Initial assessment should distinguish between used only hCG [28, 29], however this may preclude
hyper- and hypogonadotrophic hypogonadism. Hav- an optimal response in those IHH men with no prior
ing made the diagnosis, it is essential to identify the pubertal development [12, 28, 30]. Human menopaus-
needs of the patient and design a specific treatment al gonadotrophin (HMG), a urine-derived source of
tailored towards their needs, with a physiological FSH, has been shown to induce spermatogenesis in
rather than a pharmacological approach. Treatment men with HH, but this preparation also contains LH,
with testosterone alone can develop and maintain which adds a further variable in the treatment [30].
secondary sexual characteristics and enhance libido, Additionally, the urinary gonadotropin preparations
but TV is reduced and direct or indirect administra- such as HMG had to be administered by intramuscular
tion of gonadotrophins is required to induce spermato- injection, but recombinant preparations are now avail-
genesis. Treatment options include GnRH by pump, able that can be self-administered by subcutaneous
182 HOWLES et al.
injection, with important implications for clinical the initial regimen was reported to be in the range of
management [24, 31–33]. 1,000 to 2,000IU of hCG once a week [37]. If the
In the presence of complete hypophysectomy [34, bone age is significantly advanced, the dose should
35] treatment with an FSH/LH preparation (HMG) can be given three times a week. In all cases, clinical
restore spermatogenesis, but the Leydig cells are not response must be monitored, and testosterone levels
adequately stimulated. The addition of hCG stimu- measured every 2 to 3months, with dose adjustment
lates Leydig cells to produce testosterone, promoting as required to reach an optimal schedule and to avoid
testicular growth with restoration of potency and nor- side effects such as gynaecomastia. Increasing doses
mal ejaculates. Using hCG instead of direct testoster- may have a down-regulating effect and reduce testic-
one replacement yields more stable androgen levels, ular stimulation, and reduced or less frequent dosing
and there is less fluctuation in hypogonadal symptoms. may produce a better result. The use of gonadotro-
hCG treatment can also stimulate sufficient intra- phins in the treatment of adolescent boys can be im-
testicular testosterone to allow the initiation of spermato- portant not only from the point of view of developing
genesis [29, 30]. Mancini et al. [36] demonstrated secondary sexual characteristics and fertility potential
that hCG has a stimulating effect on the spermato- but also for normal psychosexual maturation [38, 39].
gonial phase, while HMG stimulates all germinal
phases. The combined treatment regimen gives com- Induction of spermatogenesis
plete recovery of spermatogenesis, full development of
Leydig cells, repair of Sertoli cells and disappearance HH is a rare cause of infertility, but it is specifically
of hyalinisation. responsive to appropriate hormone treatment. In men
who wish to achieve fertility, initial testicular volume
Induction of secondary sexual development and prior treatment determine the response to treat-
ment [12, 40] as well as the presence of cryptorchi-
When prepubertal boys are diagnosed as having hy- dism [41]. Although the resulting sperm counts are
pogonadotrophic hypogonadism such as Kallmann’s usually below the normal range (<20 million per ml),
syndrome or combined pituitary hormone deficiency, pregnancies can still be achieved. Burris et al. [42]
the patients’ desirable adult height should be taken defined the minimal number of sperm needed for con-
into account. Since gonadal replacement therapy, such ception, in men with isolated hypogonadotrophic hypo-
as hCG-hMG/FSH or testosterone treatment usually gonadism (IHH) who became sperm-positive during
induces rapid pubertal maturation even at low doses, it gonadotropin therapy. Twenty-two of 24 men (92%)
is often difficult to mimic the slow, normal pubertal proved fertile, initiating a total of 40 pregnancies. The
developmental pattern. Pubertal height gain in normal mean (+/– standard error of the mean) sperm concen-
height children is around 30cm according to Japanese tration at the time of conception was16.7+/–4.0×
standard data. The method for gaining 30cm of 106/ml. However, 71% of pregnancies were conceived
pubertal growth has not yet been established with when the mean sperm concentration was less than
hCG-hMG/FSH therapy or testosterone treatment and 20×106/ml; in 16%, the mean sperm concentration
therefore gonadal replacement treatment tends to start was less than 1×106/ml. A value of 1.5×106/ml is
later than the normal pubertal age so as to obtain the commonly used in clinical reports as representative of
patients’ desirable adult height. There are some at- a sperm concentration compatible with pregnancy [43–
tempts to mimic slow normal pubertal development 47]. Recently the use of assisted reproductive tech-
using testosterone ointment or low doses (500IU) of niques such as intracytoplasmic sperm injection (ICSI)
HCG, but it should be born in mind that height and has also been applied in HH men undergoing gonad-
bone age at start of gonadotrophin replacement therapy otrophin therapy [48–50] with better sperm quality
is closely related to adult height. rates and pregnancy being obtained with prolonged
Data from US clinical practice AACE Guidelines gonadotrophin treatment [48].
[10], also recommends that peripubertal boys with HH A TV of less than 4ml indicates that the onset of
and delayed puberty can be treated with injections of HH occurred before pubertal development, and these
hCG. Again, the stage of bone development should be patients usually require therapy with both hCG and
taken into account, and if the patient is still growing, FSH to induce spermatogenesis. Men with partial
DIAGNOSIS AND TREATMENT OF MALE HYPOGONADOTROPHIC HYPOGONADISM 183
gonadotropin deficiency, or who have previously been infant after 62months of treatment. Of those remain-
stimulated with hCG to induce pubertal development ing, four achieved normal sperm counts, two were
may initiate and maintain sperm production with hCG oligospermic, one was azoospermic, and one was not
only. Men with postpubertal acquired HH and who evaluated. Testis volume increased in all patients, and
have previously had normal production of sperm may overall 9 out of the 13 achieved normal sperm counts.
also initiate and maintain spermatogenesis with hCG Although all of the patients had been assessed by hCG
treatment only. Therapy with hCG is generally begun and GnRH challenge tests, there was no correlation be-
at 1000 to 2000IU two to three times a week, and tes- tween the responses to treatment and the test results;
tosterone levels should be monitored monthly to deter- neither test was predictive for spermatogenesis after
mine whether any adjustments are needed to normalize hCG-hMG treatment. The authors recommended
the levels. Normal levels of testosterone may require 2 starting with the second (higher) dosage schedule in
to 3months of treatment. When testosterone levels are order to obtain early spermatogenesis.
in the normal range, testicular growth and semen as- Miyagawa et al. [4] reviewed 30years of experience
sessments should be monitored monthly. If spermato- at University affiliated male infertility centres in order
genesis has not been initiated within 6 to 12months of to determine the outcome of long-term therapy with
hCG therapy, an FSH preparation should be added to hCG and human menopausal gonadotropin (hMG).
hCG, at a dose of 75IU–150IU depending on body Medical charts of 36 men aged 11 to 42years were
weight, three times a week. If pregnancy occurs, the analysed retrospectively: a total of 29 men (81%) were
regimen can be switched to hCG only, to allow contin- diagnosed with primary HH (including 5 patients with
ued spermatogenesis for subsequent potential pregnan- Kallmann’s syndrome), and 7 (19%) with secondary
cies. For long-term maintenance of secondary sexual HH. The patients were stratified according to testicu-
characteristics and fertility, it is important to consider lar volume; 23 had a TV≤4 ml, and 13 had an average
age and compliance. A combination of hCG and FSH TV of 7.5±3.5ml. Therapy was initiated with hCG
can be continued, with a lowered dose and frequency 3000IU and hMG 75IU administered by intramuscu-
during periods when another pregnancy is not desired. lar injection twice a week for 12 to 48months.
If no further pregnancies are desired, the patient can Treatment with hCG/HMG for 12 to 240months
be switched to testosterone therapy, or long-term hCG (average 56±11) resulted in sperm production for
therapy can be continued in conjunction with appro- 36% of the patients with small testes, and 71% of those
priate contraceptive measures, if needed. with large testes. Peak testosterone levels were ob-
served at 12–24months. After obtaining maximum
Clinical trials using Gonadotrophins testicular development, the doses were decreased to
biweekly injections of 3000IU hCG and 150IU hMG
I) hCG/HMG therapy if the patients wished to continue with this therapy.
Tanaka et al. [51] assessed the effects of hCG-hMG Alternatively, they were treated with biweekly injec-
treatment in 13 boys with hypopituitarism associated tions of 125 or 250mg of testosterone enanthate to
with combined growth hormone and gonadotropin maintain virilization (Table 2).
deficiency. Four of the patients had been previously
treated with testosterone enanthate by intramuscular II) hCG/uFSH therapy
injection, and one patient had been unsuccessfully MHH patients have also been treated with hCG in
treated with a GnRH pump. The hCG-hMG treatment combination with a urinary derived FSH preparation
was started after an interval of at least one month after [39, 43, 44]. Burgues et al. [43], studied 60 men with
these pre-treatments. Treatment was started at a mean hypogonadotrophic hypogonadism, of which, 16 suf-
age of 20.4years, initiated with hCG 5000IU twice a fered from Kallmann’s syndrome, 19 from idiopathic
week and hMG once a week. Four patients achieved hypogonadotrophic hypogonadism and 25 from hypo-
normal spermatogenesis with this dose after 6 to 32 pituitarism. They received uFSH (150IU×three/
weeks of treatment. The dose was increased to hCG week) and HCG (2500IU×two/week) for at least 6
5000IU twice a week and HMG 75IU twice a week in months and underwent periodic assessments of testic-
nine patients who did not achieve a normal sperm ular function. Testosterone concentrations increased
count, and one of these patients fathered a normal and all but one patient reached values in the normal
184 HOWLES et al.
Table 2. Summary of treatment and results with hCG/HMG: years and 7 prepubertal males with panhypopituitarism-
associated HH (PHH) with a mean age of 18.1 (SD of
1. hCG 3000IU+hMG 75IU administered i.m. 2× weekly,
3.24) years. HCG at a dose of between 1,000–1,500
for 12–48months
2. After obtaining maximum testicular development, this was IU and uFSH 75–100IU were administered together
reduced to hCG 3000IU+hMG 150IU, i.m., at biweekly every alternate weekday from the beginning of therapy
intervals, or treatment was changed to testosterone until complete induction of puberty and spermatogene-
enanthate 125 or 250mg biweekly i.m.
sis was achieved. All patients achieved normal sexual
3. Duration of treatment was for 12–240months, average
maturation and normal or nearly normal adult male
56±11months
levels of testosterone. Maximum increase in testicular
4. The main outcome parameters measured were testicular
volume, serum testosterone levels, sperm count, and pubic size was achieved after 32months (average 10.4ml) in
hair. the IHH group and 31months (average 15.3ml) in the
PHH group. Four patients in the IHH group and six
patients in the PHH group achieved a normal testicular
range. At the end of treatment, 48 patients (80.0%) volume (>=12mL), [52]. There was no significant
had achieved a positive sperm count. The maximum difference in the maximum testicular volume between
sperm concentration during treatment was 24.5+/– 8.1 the 2 groups. Positive sperm production was assessed
×106/ml (mean+/–SEM). The median time to induce in four of five patients with isolated HH and in three of
spermatogenesis was 5months. There was no signifi- three patients with panhypopituitarism associated HH.
cant difference in the spermatogenic response between Poor sperm production was related to the presence of
the different diagnostic groups. The rate of complete cryptorchidism as previously reported by [41].
responses in patients with isolated HH (63%) was simi- In a subsequent study, Liu et al. [33], evaluated
lar to that observed in patients with multiple pituitary potential predictors of response in 29 consecutive
deficiencies (68%). Treatment efficacy was however gonadotrophin-deficient men all desiring paternity who
significantly related to the onset of hypogonadism. received 43 courses of therapy in one centre between
Thus, in patients diagnosed with hypogonadism before 1982 and 1998. The Kaplan-Meier survival analysis
puberty the response rate at the end of treatment was estimates of median (SE) time to a sperm concentra-
of 59.6%, whereas 100% of patients with postpubertal tion of >0, >5 and >20×106/ml were 5.5 (1.1), 12.4
hypogonadism showed an adequate response at 6 months (2.3) and 29.1 (1.9) months respectively. Conception
(P<0.01). Likewise, the maximum sperm concentra- occurred in 22/43 cycles (with eight men achieving
tion in patients with postpubertal onset hypogonadism two pregnancies) with a median (SE) Kaplan-Meier
(37.9×106/ml) was significantly higher (P<0.04) than estimate of 20.5 (4.7) months. The median sperm
that observed in the other patients (22.3×106/ml). concentration at conception was 5.0 (SE 2.0; range
The spermatogenic response was not significantly 0.0–59.5)×106/ml. By employing a multivariate model
related to previous treatments, although there was a to predict these same sperm thresholds and conception
trend to an improved response in patients treated with it was found that larger testicular volume at start of
gonadotrophins. Nine out of 10 (90%) patients who treatment, prior gonadotrophin therapy, completion of
had received gonadotrophins before entering the study puberty, older age, the absence of adverse fertility fac-
achieved spermatogenesis as compared to 78% in tors and the absence of multiple pituitary hormone de-
those who had not (P<0.3). ficiency predicted a favourable response. Multivariate
A multicentre study in Europe [44] was also carried modelling suggested that the two most important
out using uFSH in combination with hCG in inducing predictors of sperm output were testicular volume and
spermatogenesis in 28 men with primary, complete pubertal status. The most important potentially modi-
isolated hypogonadotrophic hypogonadism. The pri- fiable predictor was prior gonadotrophin therapy that
mary efficacy end point was a sperm density of at least led to a shorter median time to first appearance of
1.5×106mL. Twenty-five (89.3%) patients achieved sperm in a subsequent treatment. Prior androgen ther-
spermatogenesis; 18 (64.3%) of which achieved a apy was associated with a longer time to reach a sperm
density of >1.5×106/mL. concentration of 20×106/ml. However prior andro-
Barrio et al. [39] studied 7 prepubertal males with iso- gen use and partner’s age did not appear to be signifi-
lated HH (IHH) with a mean age of 15.44 (SD of 1.97) cant predictors of spermatogenesis and pregnancy.
DIAGNOSIS AND TREATMENT OF MALE HYPOGONADOTROPHIC HYPOGONADISM 185
III) hCG and r-hFSH therapy patients however remained azoospermic.
Recent clinical studies have confirmed the efficacy Warne et al. [46] conducted a meta-analysis of 4
and safety of new recombinant gonadotropin prepara- clinical trials conducted in Europe, Australia, USA and
tions as an alternative to urinary-derived hMG in the Japan, in order to assess the safety and efficacy of
management of HH [53]. Recombinant human FSH long-term treatment with r-hFSH (GONALEF®) for
(r-hFSH) is as effective in inducing spermatogenesis induction of spermatogenesis in a large number of men
as the urinary products, but it has greater purity, higher (n=100) with HH. The analysis also considered the
specific activity, is more consistent in composition, impact of baseline characteristics on efficacy outcome.
and is less antigenic allowing subcutaneous admin- The four studies were phase III, open-label, non-
istration, [54, 55]. Follitropin alfa filled-by-mass comparative multicentric studies conducted in Europe
(GONALEF®, Merck Serono, an affiliate of Merck (32 patients), USA (36 patients), Japan (22 patients)
KGa A, Darmstadt, Germany) has a high specific ac- and Australia (10 patients). All 4 studies involved 3
tivity (13,645 IU FSH/mg) and a low batch-to-batch to 6months of pre-treatment to normalize serum tes-
variability (<2% vs up to 20% for urinary products) tosterone, using hCG 1000IU 3×/week or 2000IU
[55]. It is the first r-hFSH to be filled and released in 2×/week, adjusted according to individual response.
mass units, 5.5µg being equivalent to 75IU FSH ac- This was followed by 18 months of treatment with
tivity according to the rate in vivo bioassay [55]. In r-hFSH 150IU 3×/week, with concomitant hCG. The
clinical use it has been demonstrated to improve the primary efficacy endpoint was a sperm density of at
clinical response [56–59]. The therapy also has the least ≥1.5×106/ml. Assessments were carried out
advantage of greater patient acceptance, as the injec- every 3months, and if the patients remained azoo-
tions can be self-administered subcutaneously. spermic after 6months, the dose of FSH could be in-
Bouloux et al. [45] conducted a study in 26 creased up to a maximum of 300IU 3×/week. Both
azoospermic men aged 16–48 (mean 25.9±7.7) with drugs were self-administered by subcutaneous injection.
severe IHH. Mean TV was ≤4ml, there was no A total of 100 men were enrolled for pre-treatment
evidence of pituitary or hypothalamic lesion, and no with hCG, and 81 entered the treatment phase with
illness or use of drugs that could affect testicular func- hCG and FSH. 68 patients achieved spermatogenesis
tion. Patients were pre-treated for up to 6months during the treatment phase, and the primary efficacy
with hCG (Profasi®, Merck Serono, an affiliate of endpoint of sperm concentration ≥1.5×106/ml was
Merck KGa A, Darmstadt, Germany) 2000IU twice achieved in 56 out of the 81 men (69.1%). The median
weekly. The dose was titrated after 2months to main- time to reach this endpoint was 9months in the Euro-
tain testosterone levels within the normal range, and pean study, and 6months in the other studies. Total
patients then received 18months of treatment with sperm count per ejaculate increased steadily through-
hCG in combination with r-hFSH (GONALEF®) 150 out the 18-month period, and ejaculate volume, per-
IU three times a week, which could be increased to centage of sperm with normal morphology and pro-
225IU after 9months. The primary efficacy point gressive motility also increased during treatment. All
was a sperm concentration compatible with fertility, of men showed an increase in mean testicular volume.
at least 1.5×106/ml. Secondary end points, including This pooled data from 4 clinical studies represents
mean testicular volume and secondary sexual charac- the largest international database of patients with
teristics were also assessed. The drug was well tolerat- MHH available to date, and the self-administration of
ed, and the results of this study showed that r-hFSH is follitropin alfa in combination with hCG was success-
effective in initiating spermatogenesis in the majority ful in treating the majority of the patients. Spermato-
of patients with IHH. The primary end point, a sperm genesis was successfully induced in over 85% of men
concentration of at least 1.5×106/ml was achieved in treated, and over two-thirds of the men achieved a
63% of patients, and some degree of spermatogenesis sperm count of ≥1.5×106/ml (Table 3). The two base-
was achieved in 79%. There was also a significant line parameters that were found to have a significant
improvement sperm motility and morphology, and prognostic value on efficacy outcome were mean tes-
successful pregnancies were achieved in four out of ticular volume (Fig. 1) and BMI (Table 4). Patients
seven couples who wished to conceive. The median with a BMI ≥30kg/m2 had a lower response (64.3%)
time to response in this study was 9months. Four compared to those with a BMI <30kg/m2 (88.1%).
186 HOWLES et al.
Table 3. Spermatogenesis Response in MHH patients from 4 studies treated with hCG and r-hFSH (GONALEF®) (46)
Study location
Japan N=18 USA N=29 Australia N=8 Europe N=26
Proportion of patients who achieved sperm concentration >=1.5×106/mL and time to response
Sperm Concentration >=1.5×106/mL
Yes 16 (88.9%) 23 (79.3%) 5 (62.5%) 12 (56.2%)
No 2 (11.1%) 6 (20.7%) 3 (37.5%) 14 (53.8%)
95% Exact Confidence Interval (65.3%, 98.6%) (60.3%, 92.0%) (24.5%, 91.5%) (26.6%, 66.6%)
Responders: Time (Months) to Sperm
Concentration >=1.5×106/mL
Median 6–9 9 9 12
Range (3, 15) (3, 18) (9, 12) (3, 18)
Proportion of patients who achieved sperm concentration >0×106/mL and time to response
Sperm Concentration >0×106/mL
Yes 17 (94.4%) 26 (89.7%) 7 (87.5%) 18 (69.2%)
No 1 (5.6%) 3 (10.3%) 1 (12.5%) 8 (30.8%)
Responders: Time (Months) to Sperm
Concentration >0×106/mL
n 17 26 7 18
Median 6 6 6 6–9
Range (3, 12) (3, 12) (3, 12) (3, 18)
Total Sperm count after 18months of treatment
Total Sperm Count (×106)
Mean (SD) 34.1 (47.8) 29.6 (60.5) 25.8 (45.3) 32.5 (68.1)
Range (0.0, 168.0) (0.0, 294.0) (0.0, 124.0) (0.0, 244.7)
Fig. 1. Relationship between baseline mean testicular volume (MTV) and chances of achieving a sperm concentration ≥1.5×106/mL
in MHH patients treated with hCG/r-hFSH (GONALEF®) [46]
Both injections were well tolerated, with only mild sults of the above studies conducted in Europe, Austra-
adverse events reported. More than 99% of the men lia and the USA. Despite the established efficacy of
reported no local site reactions. this intervention, it is possible that populations in other
GONALEF® received approval in the European regions may respond differently to treatment because
Union for the treatment of male HH based on the re- of genetic variability. Okada et al. [47] reported on a