The aim of the present study was to investigate the effects of exogenous glucocorticoids (GCs), a potent cause of male hypogonadism, on the function of the hypothalamic-pituitary-gonadal axis, and to determine their secondary effects in male patients. The present study was a case-controlled study conducted in Basrah, Iraq. Of the 152 participants who met the inclusion criteria, 100 patients used different types of GCs. Of these 100 patients, 57 patients (57%) were current GC users, and 43 patients (43%) were not currently using GCs (had not used GCs in the past 30 days). The control group was comprised of 52 men (34.21%), considered as healthy participants, although 7 men (13.65%) were biochemically diagnosed with hypogonadism. Current GC exposure significantly decreased the total and free testosterone levels, whereas previous GC exposure increased estradiol (E2) levels, with the 31 patients on oral dexamethasone (cumulative dose, 18.9 mg) exhibiting a 7.5-fold increased risk of being diagnosed with hypogonadism. For previous GC users, a significant increase in the E2 level was observed, whereas all other gonadal hormonal levels were within normal reference ranges, including the total and free testosterone levels. The total cumulative dose of equivalent GCs was 240 mg, which resulted in a decrease in total testosterone levels, and subsequent hypogonadism. Oral dexamethasone at a lower total cumulative dose resulted in hypogonadism.
Male hypogonadism is a clinical syndrome in which the diagnosis is dependent on hypogonadal signs or symptoms and unequivocally low serum testosterone (T) levels (
The term secondary hypogonadotropic hypogonadism refers to the insufficient release of gonadotropin-releasing hormone (GnRH) with low to normal FSH, LH and T levels. The causes of secondary hypogonadism include the following: i) Hyperprolactinemia (often secondary to pituitary adenoma), ii) GnRH deficiency with anosmia (Kallmann syndrome), iii) hypothalamic lesions or disorders, and iv) pituitary lesions or disorders (
Hypogonadism has several symptoms, including sexual dysfunction, lethargy, depressed mood, poor concentration and memory, mild anemia, and a diminished sense of well-being (
GC abuse is another cause of male hypogonadism (
Exogenous GC causes an acute reduction in T levels in men by directly suppressing gonadal steroid secretion; thus, GC therapy frequently and significantly decreases the serum T levels. Furthermore, this effect appears to be mediated by the suppression of GnRH secretion by the hypothalamus (
The decrease in the total T (TT) and free T (FT) levels in men who use GCs may be attributed to GC binding to GC receptors located in several tissues and organs in the body, such as the Leydig cells, decreasing T biosynthesis via 11β-HSD1 reductase activity (
The aim of the present study was to investigate the effects of exogenous GC use, considered a potent cause of male hypogonadism, on the function of the hypothalamic-pituitary-gonadal (HPG) axis, and to determine any secondary effects in male patients.
The present study was approved by the Faiha Specialized Diabetes, Endocrine and Metabolism Center. Each participant provided written informed consent. Before providing consent, patients were provided with a sufficient explanation to ensure that each patient clearly understood the nature of the study.
The present study was a case-controlled study performed at Faiha Specialized Diabetes, Endocrine and Metabolism Center (FDEMC) in Basrah, Iraq. The study was performed between June 2017 and June 2018. All participants were admitted to FDEMC due to an endocrine disorder. In addition to clinical examination, age and medical history (for example, smoking history) were obtained as shown in
Using prepared study questionnaires, patients were asked about the following: i) Type of steroid used (oral/parenteral/depot injections); ii) method of use (prescription/nonprescription); iii) estimated total equivalent cumulative dose; and iv) current or previous GC use.
The inclusion criteria were adult males aged 18-55 years who were currently using or at any time in the previous year used GCs at a dose of 7.5 mg prednisolone or equivalent for at least 10 days, regardless of their symptoms or causes of referral; based on the criteria used by Crawford
The exclusion criteria were any patients with at least one of the following: History of orchitis; undescended testis (unilateral or bilateral) and unilateral or bilateral testicular volume <4 ml; established atherosclerosis or cardiovascular disease; concomitant use of known erectile dysfunction-induced medications (such as antidepressants or opioids); history of spine injury; patients who had previously undergone prostate surgery; history of radiation therapy to the pelvic area; patients who had previously undergone surgery to the external genitalia and patients with an acute illness for the past month; history of critical illness requiring intensive care unit or coronary care unit admission in the past 3 months (
Of the 187 participants enrolled in the present study, 35 were excluded and 100 used different types of GC (median age, 37 years; range 17-50 years). Of the GC users, 57 patients (57%) were current GC users (median age, 37 years; range 17-50 years), and 43 patients (43%) were not currently using GCs (median age, 36 years; range 17-49 years). The control group was comprised of 52 participants (34.21%) who were considered healthy (median age, 38 years; range 19-49 years), with 7 participants (13.65%) being biochemically diagnosed with hypogonadism.
Body hair thickness, presence of gynecomastia, testicular volume, pubic and axillary hair assessment, and wrinkling around the face were physically examined to assess the presence of hypogonadism. Signs of steroid use including moon face, buffalo hump, supraclavicular fat pad, thin skin, abdominal obesity, striae, proximal muscle weakness, bruises and petechiae were assessed. Furthermore, a thorough physical examination was performed.
Anthropometric analysis including body weight and height measurements was performed with the patient wearing light clothes and no shoes, using a stadiometer (SECA-763™). Body mass index was calculated using the following formula: Weight (kg) divided by height (m)2.
Blood pressure was measured using an electronic Omron HEM-780 automatic upper arm blood pressure monitor (Omron Healthcare), with two readings 5 min apart, and the average blood pressure was taken. Hypertension was diagnosed if the patient was previously or currently taking medications to treat hypertension and had a systolic blood pressure ≥140 mmHg and/or diastolic blood pressure of 90 mmHg.
For each patient, 10 ml venous blood was obtained in the morning (between 8:00 and 9:00 am). Subsequently, the blood samples were analyzed using a Cobas E411 Analyzer electrochemiluminescence immunoassay (Roche Diagnostics).
LH, FSH, dehydroepiandrosterone sulfate, ACTH, cortisol, TT, sex hormone-binding globulin (SHBG) and prolactin (PRL) levels were measured.
The serum albumin levels were measured using a Cobas C311 fully automated chemical analyzer (Roche Diagnostics). FT levels were calculated based on TT and SHBG levels using an online-based calculator (
The total cumulative GC dose for all participants currently using GCs was calculated by multiplying the duration of GC use by the equivalent GC value (
Statistical analysis was performed using SPSS version 23.0 (IBM, Corp.). Bivariate analysis was used to analyze continuous variables and frequencies, and percentages for the categorical variables. A χ2 test was used to compare categorical variables, with 95% confidence intervals. A two-tailed P-value of P<0.05 was considered to indicate a statistically significant difference. Receiver operating characteristic (ROC) curves were used to compare the predictive value of the different statistical values, the area under the curve (AUC) and the cutoff values, with both the sensitivity and specificity values were obtained.
General characteristics of the entire cohort are presented in
Based on the hormonal assessments, the mean TT level was 391.64±208.38 ng/dl, the mean FT level was 8.90±5.93 ng/dl and the mean SHBG level was 34.42±25.47 nmol/l. The mean FSH level was 4.54±3.58 mlU/ml, the LH level was 5.82±3.82 mlU/ml, the prolactin level was 14.55±9.04 S and the mean estradiol level was 19.11±12.57.
Laboratory markers of the hypothalamic pituitary adrenal axis in patients using GCs were as follows: ACTH levels, 33.42±26.71 pg/ml; DHEA-S levels, 129.37±123 µg/dl; and cortisol levels, 11.90±11.23 µg/dl.
The effect of current GC use on the HPG axis is shown in
The effects of discontinuing GCs on the HPG axis is shown in
Patients who were previously using GCs had a mean E2 level of 22.33±10.70 pg/ml, whereas patients who were currently using GCs had a mean E2 level of 19.83±13.54 pg/ml, and this difference was significant. The subgroup analysis of these different GC formulations showed that only prednisolone PO (tablets), dexamethasone PO, and betamethasone acetate injections were statistically significantly associated with hypogonadism (P=0.018, 0.009 and 0.002, respectively).
The area under the curve (AUC) based on the receiver operating characteristics (ROC) demonstrated that there was a 3.7-fold increase in the risk of hypogonadism in patients who used a total cumulative equivalent dose of >240 mg, and this increased risk was most likely due to GC use, with a specificity of 81% and a sensitivity of 50% (P=0.038;
Regarding the 31 patients using dexamethasone PO, the risk of hypogonadism was 7.5-fold if they were taking a total dexamethasone cumulative dose of >18.9 mg, with a sensitivity and a specificity of 67 and 73%, respectively (P=0.015;
The formulations of dexamethasone injection and methylprednisolone acetate were not statistically associated with hypogonadism (
There was a significant association between the current use of GCs and the state of hypogonadism (23 patients; 40%) compared with those who previously used GCs, (3 patients; 7%; P<0.0001). This association was primarily due to use of oral dexamethasone use in (12 patients; 39%).
In the present study, in patients currently using GC, hypogonadism manifested as low TT levels in <50% of the study sample. These results are comparable to a cross-sectional study by Morrison
Furthermore, TT and FT levels in patients currently using GC with different formulations were significantly decreased, similar to a cross-sectional study by Contreras
One of the significant findings in the present study was the increase in E2 levels in patients with a history of previous GC use, whilst the other HPG axis functions were normal. The mechanism underlying the increased E2 levels in patients who previously used GC is unclear, but may be associated with the activation of the aromatase enzyme after the TT levels return to normal; as proposed by a retrospective multicenter study by Tan
The TT and FT levels returned to their normal reference ranges in patients who previously used GC compared with those currently using GC. This is likely due to the recovery of the HPG axis following drug withdrawal, consolidating the idea of causality of low TT levels in GC users.
There was a 4-fold increased risk of hypogonadism (low TT levels) in patients currently using GC compared with GC-naive patients. A similar study assessing the risk of causality of hypogonadism in patients using GCs has not been performed, to the best of our knowledge.
Regarding hypogonadism, according to the type of GC administered/used, >50% of the patients on oral prednisolone developed hypogonadism compared with those who were not using GCs. Morrison
Regarding other types of GC, in the present study, it was observed that oral dexamethasone resulted in less hypogonadism compared with injectable betamethasone and the control group who never used GCs, warranting further studies on the differences of different GC formulations in hypogonadism.
An extensive study assessing the effects of different types of GC on the HPG axis similar to our study has not been conducted yet, to the best of our knowledge. Most studies use one or two types of GC only such as the case-control study by MacAdams
Compared with the 240-mg total cumulative equivalent cutoff dose of prednisolone in the present study causing hypogonadism, the effects of GCs on gonadal function were confirmed by Morrison
Contreras
In MacAdams
Oral dexamethasone use results in hypogonadism at lower total cumulative doses when compared with other types of GC, and this may be associated with the longer half-life of dexamethasone, reaching up to 3 days, compared with other GC types (
Hypogonadism affected half of study sample using GCs, and may be reversible. Based on the results of the present study, there was marked hypogonadism in patients currently using GC with a total cumulative dose of 240 mg (equivalent to prednisolone as shown in
An increase in E2 levels was observed in patients previously using GCs, whilst all the other gonadal hormones, and in particular TT, were within the normal ranges.
The present study has some limitations. Firstly, the present study was a cross-sectional case-controlled study, with limited external validity, and thus the observations are not generalizable. The present study was performed using a relatively homogenous high-risk population, and as with all observational data analyses, it was not possible to establish causality from an association. Additionally, the sample size was small, and a single-center study. Finally, due to the short duration of the study, it was not possible to follow up the patients for assessment of future complications.
A prospective longitudinal study is required to evaluate patients who withdraw the use of GCs to assess the reversibility and the temporal relation of the recovery of the HPG axis.
An awareness campaign is required to reduce the use of GCs among the general population, which are considered as dangerous drugs with several side effects, including hypogonadism as a serious complication.
If GCs are prescribed for any condition, it should be advised to avoid oral dexamethasone as it may result in hypogonadism with even low doses compared with other types of GC.
The authors would like to thank Dr Nassar Taha Yassin, Dr Haider Ayad and Mr Ali Hamza (FDEMC) for providing medical writing support.
No funding was received.
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
AGM and JHA were responsible for the preparation and drafting of the Introduction and Discussion. AGM and AAM were responsible for the preparation and drafting of the Materials and methods. AGM performed the statistical analysis and was responsible for the preparation and drafting of the Results and the final manuscript. AGM, AAM and JHA critically revised the manuscript for important intellectual content. All authors have read and approved the final manuscript.
The present study was approved by the Faiha Specialized Diabetes, Endocrine and Metabolism Center (Basrah, Iraq). Each participant provided written informed consent.
Not applicable.
The authors declare that they have no competing interests.
Receiver operating curves. (A) Receiver operating characteristic curve of the effect of a cumulative dose of 240 mg glucocorticoids on hypogonadism. (B) Receiver operating characteristic curve of the cumulative dose of dexamethasone on hypogonadism.
Glucocorticoid equivalent.
Potency relative to hydrocortisone | Half-life | ||||
---|---|---|---|---|---|
Treatments | Equivalent glucocorticoid, mg | Anti-inflammatory | MC | Plasma, min | Duration of action, h |
Short acting | |||||
Hydrocortisone | 20 | 1 | 1 | 90 | 8-12 |
Cortef, Cortisol | 25 | 0.8 | 0.8 | 30 | 8-12 |
Intermediate-acting | |||||
Prednisone | 5 | 4 | 0.8 | 60 | 12-36 |
Prednisolone | 5 | 4 | 0.8 | 200 | 12-36 |
Triamcinolone | 4 | 5 | 0 | 300 | 12-36 |
Methylprednisolone | 4 | 5 | 0.5 | 180 | 12-36 |
Long-acting | |||||
Dexamethasone | 0.75 | 30 | 0 | 200 | 36-54 |
Betamethasone | 0.6 | 30 | 0 | 300 | 36-54 |
Mineralocorticoid | |||||
Fludrocortisone | 0 | 15 | 150 | 240 | 24-36 |
Aldosterone | 0 | 0 | 400+ | 20 | - |
Cortef, generic name for hydrocortisone.
General characteristics of the study population.
Variables | n, % or mean ± standard deviation |
---|---|
Median age, years (range) | 37 (17-50) |
Smoker | |
Yes | 107 (70.40) |
No | 45 (29.60) |
BMI, kg/m² | |
Total Testosterone, ng/dl (range) | 391.64±208.38 (246-916) |
Free Testosterone, ng/dl | 8.90±5.93 |
Sex hormone-binding globulin, nmol/l (range) | 34.42±25.47 (10-60) |
Follicle stimulating hormone, mlU/ml (range) | 4.24±2.71 (1-13) |
Luteinizing hormone, mlU/ml (range) | 5.82±3.82 (1-9) |
Prolactin, nmol/l (range) | 14.55±9.04 (4-30) |
Estradiol, pg/ml (range) | 19.11±12.57 (range) |
Effect of current glucocorticoid use on the hypothalamic-pituitary-gonadal axis.
Factors | Currently using glucocorticoids |
Healthy controls |
P-value |
---|---|---|---|
Total testosterone, ng/dl | 318.08±209.61 | 430.40±166.59 | <0.001 |
Free testosterone, ng/dl | 7.05±4.09 | 9.97±5.49 | <0.001 |
Sex hormone-binding globulin, nmol/l | 32.11±27.47 | 35.55±27.35 | 0.492 |
Follicle stimulating hormone, mlU/ml | 4.24±2.74 | 3.98±2.19 | 0.569 |
Luteinizing hormone, mlU/ml | 5.64±4.99 | 5.88±3.12 | 0.745 |
Prolactin, ng/ml | 15.47±11.06 | 14.14±8.16 | 0.509 |
Estradiol, pg/ml | 19.83±13.54 | 16.22±12.66 | 0.185 |
aP<0.001.
bMean ± standard deviation.
Effect of discontinuation of glucocorticoid use on the hypothalamic-pituitary-gonadal axis.
Factors | Previous glucocorticoid use |
Healthy controls |
P-value |
---|---|---|---|
Total testosterone, ng/dl | 489.81±236.22 | 430.40±166.59 | 0.119 |
Free testosterone, ng/dl | 10.08±6.26 | 9.97±5.49 | 0.926 |
Sex hormone-binding globulin, nmol/l | 39.37±22.30 | 35.55±27.35 | 0.449 |
Follicle stimulating hormone, mlU/ml | 3.68±2.31 | 3.98±2.19 | 0.498 |
Luteinizing hormone, mlU/ml | 5.68±2.97 | 5.88±3.12 | 0.743 |
Prolactin, ng/ml | 15.13±7.70 | 14.14±8.16 | 0.567 |
Estradiol, pg/ml | 22.33±10.70 | 16.22±12.66 | 0.022 |
aP<0.05.
bMean ± standard deviation.
Frequency of hypogonadism among patients currently using glucocorticoids compared with individuals who had never used glucocorticoids.
Hypogonadism, n (%) | |||||
---|---|---|---|---|---|
Treatments | Yes | No | Odds ratio | Confidence interval | P-value |
Glucocorticoid | 4.34 | 1.67-11.31 | <0.001 |
||
User | 23 (40.4) | 34 (59.6) | |||
Not user | 7 (13.5) | 45 (86.5) | |||
Prednisolone PO | 8.57 | 1.57-46.71 | 0.018 |
||
User | 4 (57.1) | 3 (42.9) | |||
Not user | 7 (13.5) | 45 (86.5) | |||
Dexamethasone PO | 2.87 | 1.26-6.52 | 0.009 |
||
User | 12 (38.7) | 19 (61.3) | |||
Not user | 7 (13.5) | 45 (86.5) | |||
Dexamethasone PO, Cumulative dose | 7.5 | 1.46-38.28 | 0.015 |
||
≥18.9 mg | 8 (66.7) | 4 (33.3) | |||
<18.9 mg | 4 (21.1) | 15 (78.9) | |||
Dexamethasone injection | 1.85 | 0.29-11.6 | 0.47 | ||
User | 1(25) | 3(75) | |||
Not user | 7 (13.5) | 45 (86.5) | |||
Methylprednisolone acetate injection | 3.3 | 1.2-9.01 | 0.047 |
||
User | 4 (44.4) | 5 (55.6) | |||
Not user | 7 (13.5) | 45 (86.5) | |||
Betamethasone acetate injection | 4.33 | 1.87-10.02 | 0.002 |
||
User | 7 (58.3) | 5 (41.7) | |||
Not user | 7 (13.5) | 45 (86.5) | |||
Total cumulative equivalent dose | 3.72 | 1.05-13.22 | 0.038 |
||
≥240 mg | 9 (64.3) | 5 (35.7) | |||
<240 mg | 14 (32.6) | 29 (67.4) |
aP<0.05,
bP<0.01,
cP<0.001. PO, per Orem.
Frequency of hypogonadism among patients currently using glucocorticoids compared with patients who had previously used glucocorticoids.
Hypogonadism, n (%) | |||||
---|---|---|---|---|---|
Treatments | Yes, n=26 | No, n=74 | Odds ratio | Confidence interval | P-value |
Glucocorticoid | 0.11 | 0.03-04 | <0.0001 |
||
Current user | 23 (40.40) | 34 (59.60) | |||
Previous user | 3 (7.00) | 40 (93.00) | |||
Prednisolone PO | 0.12 | 0.01-1.67 | 0.133 | ||
Current user | 4 (57.10) | 3 (42.90) | |||
Previous user | 1 (14.30) | 6 (85.70) | |||
Dexamethasone PO | 0.05 | 0.01-0.42 | <0.0001 |
||
Current user | 12 (38.70) | 19 (61.30) | |||
Previous user | 1 (3.10) | 31 (96.90) | |||
Dexamethasone injection | 1.33 | 0.75-2.34 | 0.444 | ||
Current user | 1 (25.00) | 3 (75.00) | |||
Previous user | 0 (0.00) | 5 (100.00) | |||
Methylprednisolone acetate injection | 0.45 | 1.29-1.56 | 0.208 | ||
Current user | 4 (44.40) | 5 (55.60) | |||
Previous user | 3 (20.00) | 12 (80.00) | |||
Betamethasone acetate injection | 2.40 | 1.22-4.68 | 0.069 | ||
Current user | 7 (58.30) | 5 (41.70) | |||
Previous user | 0 (0.00) | 4 (100.00) |
aP<0.001. PO, per Orem.