There were 18 male patients with idiopathic or functional hypogonadotropic
hypogonadism. The patients’ characteristics are presented in Table 1. The mean age was
44.3±6.3 (SD) years (range 21-67 years). The mean BMI was 29.9±4.5 (range 18.5-37.6).
One patient was borderline underweight and one was a class II obese. None of the
patients suffered from chronic diseases, including overt components of the metabolic
syndrome, besides overweight (4). Twelve of the patients presented with decreased libido
and/or erectile dysfunction, 3 complained of fatigue or tiredness, 6 suffered from a range
of emotional or psychological-mental disorders including, anxiety, depression, post-
trauma distress (PTSD) and attention deficit. Two of the patients had histories of cranial
pathology: head trauma and removal of a para-sellar dermoid cyst, respectively. Two
were referred for evaluation because of infertility and turned out to be hypogonadal, 2
were referred because of gynecomastia, 3 had decreased bone mineral density and one
had arrested sexual maturation which coinciding with a diagnosis of attention deficit
disorder, an eating disorder and was treated with sertraline.
Initial individual responses of total testosterone, LH and FSH are presented in
Figure 1. Mean basal total testosterone was 7.6±2.6 nmol/L, and increased to 19.3±5.2
nmol/L following clomiphene treatment (P< 0.0001; paired t-test). Mean basal LH was
2.7±2.1 mIU/L, and increased to 8.3±3.5 nmol/L following clomiphene treatment (P<
0.0001; paired t-test), and mean basal FSH was 4.2±3.6 mIU/L, and increased to 8.6±6.2
nmol/L following clomiphene treatment (P= 0.007; paired t-test). A significant
correlation was observed between post-treatment LH and post-treatment FSH (r 2 - 0.33;
P= 0.02). A borderline significant correlation was observed between post-treatment total-
testosterone and post-treatment LH (r 2 - 0.25; P= 0.049). There were no significant
correlations between basal and post-treatment total testosterone, basal and post-treatment
LH or basal LH and post-treatment total testosterone. Biochemical responses were
observed irrespective of BMI.
Figure 2 illustrates changes in serum total testosterone in response to dose
modifications of clomiphene citrate, in two patients.
Twelve patients (67%) reported subjective improvement in symptoms, including
libido, fatigue, and gynecomastia. Spontaneous pregnancy occurred in the wife of a
patient (#7) who was initially referred for investigation of infertility.
Most of the patients presented no adverse effects, except for one, who experience
transient nipple tenderness, without apparent gynecomastia, while treated with a 50 mg/d
dose, which subsided upon stopping the treatment, and did not recur following
resumption of the treatment with a reduced, 25 mg/d, dose.
Discussion
Our series adds to a considerable body of existing data indicating that clomiphene
citrate may be a suitable alternative to exogenous testosterone in a considerable number
of men with functional hypogonadotropic hypogonadism (13). The present report
provides a unique insight to the individual biochemical responses to the treatment.
Notably, marked responses were also observed in 2 patients with histories of cranial
pathologies (#1, #8), 2 patients with somewhat elevated basal FSH (#5, #16) and one
with an eating disorder (#15). Thus, a history of cranial pathology, per-se, and functional
hypogonadotropic hypogonadism may not always be mutually exclusive. Clomiphene
may also be useful in some patients with functional hypogonadotropic hypogonadism
combined with an apparent primary spermatogenetic defects (elevated FSH). Accordingly,
Shabisigh et al. (14) reported response to clomiphene in 2 patients following orchiopexy
for cryptorchidism and one with a “known genetic abnormality”. Our experience with
patient #15 suggests that clomiphene may also overcome the inhibitory effect of
sertraline on testosterone production and LH secretion, as previously observed in rats
(15). Neither basal testosterone nor basal LH predicted testosterone response to
clomiphene in our patents.
Limitations of our study include the retrospective, observational data collection, a
relatively small, mixed, sample, lack of a formal androgen-deficiency symptoms
assessment, lack of genetic analyzes which could have better characterize the patients
populations and short follow-ups. Nevertheless, all our patients presented favorable
biochemical responses and 2/3 of them reported considerable improvement in their
androgen-deficiency symptoms.
Clomiphene citrate is a mixture of the trans-isomer (enclomiphene), a pure
estrogen antagonist, and the cis-isomer (zuclomide), a weakly estrogenic compound (16).
Clomiphene was initially approved by the FDA in 1967 for ovulation induction in women
with dysfunctional ovulation desiring pregnancy. The stimulatory effect of clomiphene
on testosterone secretion in men, via stimulation of gonadotropin pulsatility and secretion
(17–19), was recognized early on, and was attributed to its anti-estrogenic properties,
decreasing estrogen-induced inhibition of gonadotropins secretion at the hypothalamic
level (20, 21).