Treatment with human chorionic gonadotropin for PADAM: A preliminary report

Abstract

The purpose of this study was to evaluate the efficacy and safety of human chorionic gonadotropin (hCG) for patients with partial androgen deficiency of the aging male (PADAM). Twenty-one patients over 50 years of age with PADAM symptoms were included in this study. Laboratory and endocrinologic profiles were reviewed as appropriate, and PADAM symptoms were judged by means of several questionnaires such as the Aging Males' Symptoms (AMS) scale, short version of the International Index of Erectile Function (IIEF-5), and the Self-rating Depression Scale (SDS). Laboratory and endocrinologic values and symptom scores were evaluated and compared before and after treatment by hCG injection. The treatment period was 8.0 ± 5.0 months (3.0 – 24.0 months). Serum concentrations of testosterone, including total testosterone, calculated free testosterone, and calculated bioavailable testosterone, increased significantly. AMS total scores and subscores decreased significantly after treatment. However, IIEF-5 and SDS scores did not improve. With respect to adverse effects, laboratory tests showed that only red blood cell count, hematocrit and hemoglobin level increased significantly after treatment, however, these values remained within the normal range. No adverse effect was identified after treatment. We conclude that hCG injection may be considered as a treatment for PADAM.

Keywords:

• Partial androgen deficiency of the aging male
• human chorionic gonadotropin
• Aging Males' Symptoms scale

Introduction

“Male menopause” and “symptomatic late onset hypogonadism” have received widespread attention in the popular and medical media in the last few years [1]. The International Society for the Study of the Aging Male (ISSAM) coined the acronym PADAM for “partial androgen deficiency of the aging male” to designate this condition [1]. PADAM is defined as a biochemical syndrome associated with advancing age and is characterized by a deficiency in serum androgen with or without decreased genomic sensitivity to androgen [1]. It is well known that the serum androgen level declines with age and that this decline is the main cause of PADAM. Clinical symptoms of PADAM are characterized by: 1) the easily recognized features of diminished sexual desire and erectile quality, particularly nocturnal erections; 2) changes in mood with concomitant decreases in intellectual activity, spatial orientation ability, fatigue, depression and anger; 3) decrease in lean body mass with associated diminution in muscle volume and strength; 4) decrease in body hair and skin alterations; 5) decrease in bone mineral density resulting in osteoporosis; and 6) increase in visceral fat [2-6]. The treatment of PADAM has recently received increased attention with respect to quality of life.

The first-choice treatment for PADAM is usually androgen supplementation. Hormone replacement therapy (HRT) aims to substitute the deficient hormone with a perfect copy of the natural hormone, with a dose schedule that generates physiological hormone levels over 24 hours of the day [3]. Many researchers have recommended HRT with testosterone for PADAM and have reported that HRT can improve sexual function, libido and sense of well-being, as well as maintain bone and muscle mass [7-11]. Oral and transdermal testosterone preparations, as well as injections, have been used clinically for PADAM worldwide and their efficacies have been reported. Testosterone is generally administered by injection in Japan because oral and transdermal preparations are not available. Testosterone injections produce a nonphysiologic serum testosterone level that peaks rapidly after injection and declines gradually over 2 weeks [12]. The reduction in serum testosterone is sometimes associated with near normal gonadotropin levels in aging men, suggesting the aging is associated with partial hypothalamic – pituitary dysregulation [13-15]. In addition, testosterone supplementation for long periods of time increases the risk of testicular atrophy, whereas injections of human chorionic gonadotropin (hCG) do not increase the risk of testicular atrophy because it induces the testes to produce endogenous testosterone. Furthermore, hCG has been used safely as a treatment for patients with hypogonadotropic hypogonadism or idiopathic male infertility [16-19]. However, the clinical data of hCG for PADAM has not been reported well.

The purpose of this study was to evaluate the efficacy and safety of hCG for patients with PADAM by comparing endocrinologic and laboratory values, and PADAM symptoms before and after treatment.

Materials and methods

Seventy-seven men over 50 years of age with a chief complaint of decreased libido, erectile dysfunction, depression, general fatigue, or other PADAM symptom, visited one of our special clinics for PADAM at Osaka University Hospital, or an affiliated hospital, between September 2002 and June 2004. Those in whom either total testosterone (TT), calculated free testosterone (cFT) or calculated bioavailable testosterone (cBT) indicated hypogonadism according to the ISSAM's recommended cut-off levels [1], and in whom serum luteinizing hormone (LH) concentrations were within normal range, were scheduled for hCG treatment. Patients with a serious disease such as malignancy or suicidal depression, those with a high prostate-specific antigen (PSA) level (more than 4.0 ng/ml), and those refusing treatment were excluded from the study. Twenty-one patients received hCG treatment. In these patients, plasma TT was measured on two occasions, once before intramuscular injection of 10,000 IU of hCG and again 4 days later, and adequate production of testosterone in response to hCG was confirmed (3.4 ± 1.4 times) before the entry into hCG treatment (Table I).

Table I.  Production of testosterone in response to intramuscular injection of 10,000 IU of hCG.

Before (ng/ml)	4 days later (ng/ml)	response (times)
1.3 ± 0.5	4.3 ± 1.8	3.4 ± 1.4

Patients ranged in age from 50 to 79 years (55.2 ± 6.4 years). All patients were able to receive the treatment for more than 3 months, and the treatment period was 8.0 ± 5.0 months (3.0–24.0 months). All patients provided written informed consent for participation in this study. General symptoms of PADAM were judged according to the Aging Males' Symptoms (AMS) scale [20]. Erectile function and depressive state were judged according to the short version of the International Index of Erectile Function (IIEF-5) [21] and the Self-rating Depression Scale (SDS) [22], respectively. SDS is a self-reporting scale composed of 20-item scales and was developed to measure depressive symptoms using 4-point scales. Twenty items include depressed mood, morning symptoms, crying, insomnia, diminished appetite, weight loss, loss of sexual interest, constipation, palpitations, fatigue, clouded reasoning, difficulty with completing tasks, difficult decision making, restlessness, lack of hope, irritability, diminished self-esteem, life satisfaction, suicidal ideation and anhedonia [22]. Endocrinologic variables included serum LH, follicle-stimulating hormone, TT, estradiol, prolactin (PRL), growth hormone and insulin-like growth factor-1 levels. cFT and cBT were calculated on the basis of TT and sex hormone-binding globulin according to the formula included on the ISSAM website (http://www.issam.ch/freetesto.htm) [1]. Hematopoiesis, liver function, lipid profile, serum PSA, and urinary deoxypyridinoline as an index of bone resorption were also evaluated. Treatment consisted of intramuscular injection of 3,000 units hCG (ASKA Pharmaceutical Co. Ltd., Tokyo, Japan) every 2 weeks. All blood samples were collected at the nadir of serum testosterone concentration (2 weeks after the last injection and just prior to the next injection) between 09:00 and 11:00 hours for monitoring of endocrinologic variables. Laboratory and endocrinologic values and PADAM symptoms were compared before and after treatment to evaluate the efficacy and safety of hCG for PADAM.

Data are presented as mean ± SD, and statistical analysis was performed with paired Student's t-test. A P value of less than 0.05 was considered statistically significant.

Results

Endocrinologic values before and after hCG treatment are shown in Table II. Serum concentrations of TT, cFT, and cBT increased significantly, as expected, and PRL decreased significantly. No other endocrinologic variables, including LH, were altered. With respect to PADAM symptoms, AMS scores decreased significantly after treatment. Furthermore, each of the AMS subscores (psychological, somatovegetative, sexual) decreased significantly. No significant improvement was observed in IIEF-5 or SDS (Table III). With respect to laboratory values, red blood cell count, hematocrit, and hemoglobin level increased significantly after treatment (Table IV). No other laboratory values showed significant alterations. There was also no increase in PSA level. No adverse events of sleep disorders and worsened urinary symptoms such as dysuria, pollakisuria, nocturia and weak stream were identified after treatment.

Table II.  Endocrinologic values before and after HRT in patients who received hCG injections.

	Normal range	Pre-HRT	Post-HRT	P
TT (ng/ml)	2.7–10.7	2.1 ± 0.5	2.7 ± 0.7	<0.01
cFT (pg/ml)	–	52.7 ± 13.2	65.4 ± 22.3	<0.05
cBT (ng/ml)	–	1.2 ± 0.3	1.5 ± 0.5	<0.05
E2 (pg/ml)	20–60	28.9 ± 11.0	28.5 ± 11.9	NS
LH (mIU/l)	1.7–11.2	4.0 ± 2.4	4.2 ± 3.1	NS
FSH (mIU/l)	2.1–18.6	10.7 ± 9.5	9.6 ± 9.3	NS
PRL (ng/ml)	0–15	16.9 ± 18.2	12.1 ± 15.2	<0.05
GH (ng/ml)	–	0.3 ± 0.3	0.4 ± 0.5	NS
IGF-1 (ng/ml)	59–215	212.6 ± 37.3	206.1 ± 44.1	NS
uDP (nmol)	2.1–5.4	3.8 ± 1.2	3.8 ± 1.2	NS

HRT, hormone replacement therapy; TT, total testosterone; cFT, calculated free testosterone; cBT, calculated bioavailable testosterone; E2, estradiol; LH, luteinizing hormone; FSH, follicle-stimulating hormone; PRL, prolactin; GH, growth hormone; IGF-1, insulin-like growth factor-1; uDP, urinary deoxypyridinoline. NS, not significant. P value calculated by paired Student's t-test.

Table III.  PADAM symptom scores before and after HRT in patients who received hCG injections.

	Pre-HRT	Post-HRT	P
AMS score	53.6 ± 9.4	42.1 ± 11.0	<0.01
psychological	15.0 ± 3.9	10.6 ± 4.1	<0.01
somatovegetative	22.7 ± 4.7	17.6 ± 5.1	<0.01
sexual	16.0 ± 2.9	14.0 ± 3.6	<0.05
IIEF-5 score	9.2 ± 6.3	10.2 ± 7.2	NS
SDS score	48.5 ± 7.3	42.6 ± 10.7	NS

HRT, hormone replacement therapy; AMS, Aging Males' Symptoms; IIEF-5, International Index of Erectile Function; SDS, Self-rating Depression Scale. NS, not significant. P value calculated by paired Student's t-test.

Table IV.  Laboratory values before and after HRT in patients who received hCG injections.

	Normal range	Pre-HRT	Post-HRT	P
RBC (x10^6/ml)	440–560	461.3 ± 24.9	476.0 ± 34.3	<0.05
Hb (g/dl)	13.8–17.0	14.4 ± 0.5	14.8 ± 0.8	<0.05
Ht (%)	41–51	42.5 ± 1.6	43.9 ± 2.4	<0.01
AST (U/l)	0–30	16.0 ± 4.7	17.6 ± 6.1	NS
ALT (U/l)	0–32	17.0 ± 4.9	21.2 ± 14.6	NS
γ-GTP (mIU/l)	9–51	37.1 ± 33.1	39.0 ± 38.4	NS
Total cholesterol (mg/dl)	150–220	207.7 ± 31.2	208.4 ± 33.8	NS
HDL cholesterol (mg/dl)	40–80	58.9 ± 40.0	51.2 ± 10.4	NS
triglyceride	30–150	236.8 ± 161.7	246.9 ± 155.4	NS
PSA (ng/dl)	0.0–2.1	1.1 ± 0.7	1.2 ± 0.8	NS

HRT, hormone replacement therapy; RBC, red blood cell; Hb, hemoglobin; Ht, hematocrit; AST, aspartate amino transferase; ALT, amino alanine transferase; γ-GTP, gamma glutamyl transpeptidase; PSA, prostate specific antigen. NS, not significant. P value calculated by paired Student's t-test.

Discussion

The efficacy of testosterone HRT for patients with PADAM has been reported [9]. With respect to somatovegetative symptoms, lean body mass and lumbar spine bone mineral density increased, and fat mass decreased, after 36 months of treatment with a testosterone patch in 108 men over 65 years of age [23],[24]. In addition, older men showed increased muscle volume, and leg and arm muscle strength, after 6 months of HRT treatment [25]. HRT treatment was reported to alleviate depressed mood in men with hypogonadism or symptomatic human immunodeficiency virus illness [26]. With respect to sexual symptoms, frequency of early morning erection, ability to maintain erection and libido, these were reportedly improved by HRT [27],[28]. Morley and Tariq have also reported that testosterone restored erections in men who had originally shown no response to sildenafil [29]. However, high-quality testosterone preparations that can maintain a physiologic testosterone level have not been available in Japan. The aging is associated with partial hypothalamic – pituitary dysregulation [13-15]. Therefore, we treated PADAM by hCG injection. We generally performed hCG injections every 2 weeks because it has been reported that the binding capacity of testicular hCG receptors is significantly reduced for 5 days after injection, begins to increase on day 7, and returns to pre-administration levels 14 days after a single administration of 5000 IU hCG [30].

Pharmacokinetic studies of hCG demonstrate a usual terminal half-life of about 30 hours, and testosterone levels usually peak between 72 and 96 hours after the hCG administration. In the present study, injection of hCG induced significant increases in serum TT, cFT, and cBT concentrations, even when measured at the nadir of serum testosterone concentration. This finding indicates a good response of the testes in producing endogenous testosterone. With respect to symptom scores, the AMS score decreased significantly after treatment. However, IIEF-5 and SDS scores did not improve significantly. hCG might not improve SDS scores because depression is a complex condition caused by physical, physiological and social factors, and not by hypogonadism alone. Indeed, we previously reported that serum cBT concentrations did not correlate with depression scores [31]. However, our current data showed improvement of the AMS psychological subscore, which indicates that hCG treatment may improve psychological status with regard to well-being, mood and cognition. A recent report showed that testosterone can increase positive and decrease negative mood, but has no effect on dysphoria or depression [9]. Our data are consistent with this finding. Likewise, the IIEF-5 score as an indicator of erectile function did not change, even though the AMS sexual subscore improved. We speculate that an increase in testosterone concentration by hCG injection improves libido, sexual arousal and sexual activity, but not erectile function. Our endocrinologic data showed a significant decrease in serum PRL concentration after treatment. It is reported that high serum PRL concentrations inhibit libido [32]. Thus, this significant decrease in serum PRL concentration may be related to improved libido.

With respect to adverse symptoms, we did not find any severe symptoms, e.g., sleep disorders, or worsened urinary symptoms such as dysuria, pollakisuria, nocturia and weak stream. Significant increases in red blood cell count, hematocrit and hemoglobin levels were the only observed adverse effects of hCG injection. Other laboratory values, including PSA level, were not altered. Many studies have found that androgens may be beneficial in the treatment of primary anemia and bone marrow failure. It is well known that testosterone therapy increases whole-body hematocrit values. Despite the short treatment period in the present study (8.0 ± 5.0 months), red blood cell count, hemoglobin level and hematocrit were increased. Another short-term study showed a rise in hematocrit of up to 7% in elderly hypogonadal men undergoing testosterone therapy [33]. Patients undergoing treatment by hCG injection, even for a short period, should be monitored for polycythemia, although our data for red blood cell count, hemoglobin level and hematocrit in our patients remained within the normal range.

We showed that hCG injection can effect a significant improvement in some PADAM symptoms and that it did not have any serious adverse effects. Although hCG injection appeared to be effective for PADAM, particularly with respect to sexual status other than erectile function and psychological status other than depression, a placebo effect cannot be ruled out. Only one double-blind, placebo-controlled, randomized study has monitored the effects of 3 months' administration of hCG to aging men with plasma testosterone levels in the lower range of normal [34]. It showed that plasma levels of TT increased 50% above baseline and the effects were very similar to those of androgen administration to aging men. Our result is consistent with this well controlled study. However, it was recently reported that none of the AMS subscores (psychological, somatovegetative, sexual) correlated significantly with TT, FT, or BT in a study of 161 healthy, ambulatory, elderly men [35]. Likewise, no correlation between AMS scores (total and subscores) and testosterone levels was reported in a study of 81 self-referred PADAM patients [36]. We have also reported that PADAM symptoms as evaluated by AMS, IIEF-5 and SDS scores were not related to serum testosterone concentration in a study of 90 self-referred PADAM patients [37]. Thus, it remains unclear whether all PADAM symptoms can be explained by a decrease in serum testosterone concentration alone, and whether HRT can improve PADAM symptoms by exerting only an endocrinologic effect. To address these issues, a controlled, randomized study, including a placebo and a large number of PADAM patients, is needed.

Conclusion

Because our study showed a significant increase in the serum testosterone concentration and a significant improvement in AMS scores, we conclude that hCG treatment may be considered a treatment option for PADAM in patients in whom adequate production of testosterone in response to hCG was confirmed.

Acknowledgements

We are very grateful to M. Omune, M. Oki, S. Tanabe, C. Nakamura and T. Enomoto (of our laboratory) for assistance in sample collection and for useful discussions.