How Low is Low Enough to be Given Testosterone Replacement Therapy in Patients with Late Onset Hypogonadism? What Should Be Evaluated? A Case Report

Background: Late Onset Hypogonadism (LOH) is a disease associated with advancing age, characterized by symptoms and a deficiency in serum testosterone. It is important to choose which patient suitable for testosterone replacement therapy (TRT), but there is no one consensus that fits for all. After treating patients with testosterone replacement therapy (TRT), several parameters need to be evaluated. Case: A 74-years old male came with chief complaint of difficulty to maintain erection since 2 years ago.. PADAM questionnaire was positive and IIEF-5 score was 6. Physical examination showed an underweight condition. Total testosterone level was 3,65ng/mL, and patient chose to be given TRT instead of evaluating his free testosterone. PDE-5 inhibitor and non-pharmacologic treatment was also given. Follow-up showed that his erection was improved. Discussions: At which level should testosterone be substituted is still debatable. Several consensuses issued by several organization still cannot be used universally. Study in Indonesia showed that symptoms of LOH had been occur when the testosterone level still in normal range. After giving TRT to our patients, routine follow up is needed. Non pharmacologic treatment also needs to be addressed to improve the outcome. Conclusions: Symptoms of LOH had been occurred even though testosterone level is still in normal range. The consideration made by clinician is the most important thing to be evaluated, whether to give TRT or not. Somatic and laboratory parameters mentioned in this study is important to be evaluated.


INTRODUCTION
Testosterone played a major role in male; it is responsible for the development and physiologic function from fetus until elderly. Testosterone changes occur in elderly related to aging. Total and free testosterone are both decreased gradually in elderly. 1 Late onset hypogonadism (LOH) defined as disease associated with advancing age characterized by symptoms and deficiency in serum testosterone. 2 Several more-specific symptoms are associated with low testosterone level, such as decreased sexual desire, erectile dysfunction, and decreased frequency of morning erections. Testosterone level should be evaluated in patients with positive ADAM's questionnaire. Several consensuses have a different cutoff value regarding low testosterone level. There is still no consensus specifically for Indonesian or Asian population, and at which level testosterone should be substituted. Before giving TRT, evaluating the absolute and relative contraindication is important. Several route of TRT administration had been provided. 3 Clinician should understand the pharmacokinetics of TRT given. Several somatic and laboratory parameters need to be assessed in different time periods. 1

CASE
A 74-years old male came to Andrology Clinic at Dr. Soetomo General Hospital with chief complaint of hard to maintain erection for the past 2 years. At first, he felt that his erection was good enough for penetration with Erection Hardness Score (EHS) 3, but now only EHS 1. These reduction in EHS is slowly but progressive since 2 years ago, up until now EHS 1. He also felt that his body is less energetic to carry out daily activities. In the last 2 years, his wife had a heart disease, so she had a regular checkup out of city, while he stayed in Surabaya. So, in these 2 years they did not regularly meet each other and did not regularly have a sexual intercourse. Sometimes also he said that his wife refuses to have a sexual intercourse because she afraid that her cardiac disease will be worse. Patient also said that sometimes when they had a sexual intercourse, he scared that sexual intercourse would provoke any deterioration in his wife's condition. About one month ago, his wife came back from out of town and her cardiac disease was now stable. Since then, they tried to have a sexual intercourse, but failed. They tried about 7 times, in that 7-occasion penetration is only successful 1 time with the help of his wife's hands, but not strong enough to penetrate until ejaculation. Because of this failure, his wife asked him to check to Andrology Clinic. Before this erection problem occur, he could do sexual intercourse 3-4 times in a week. At night, he did not feel any Nocturnal Penile Tumescence (NPT) in the last 1.5 years. His libido was also decrease since 1.5 years ago. He did not have any history of sexual intercourse beside with his wife, no history of hypertension, diabetes mellitus or other chronic disease. He had a history of bilateral inguinal hernia surgery about 10 years ago. He smokes 1 pack of cigarettes in the last 40 years ago. No history or current sexual problem found in his wife. He also said that he is still sexually attracted to his wife. PADAM questionnaire was positive, and IIEF-5 score was 6. Physical examination showed blood pressure 130/80mmHg, and other vital signs was within normal limit. He is currently in underweight BMI (14,7 kg/m2) with 163 cm in height and 39kg in weight. Other physical and genital examination was within normal limit. His laboratory examination was listed below. Based on anamnesis, physical examination, and laboratory examination, we diagnosed him with severe erectile dysfunction et causa mixed (psychogenic and late onset hypogonadism (LOH)). We educate the patients all about his disease and possible exact cause, to modify his lifestyle (doing regular exercise 3-5 times a week with a minimum of 30 minutes, modified his diet and adequate rest) and most importantly to stop smoking because smoking is related to his erectile function. We also educate about the normal aging process of sexual response and sexual changes in elderly to match his expectations about the result of the treatment we are going to give. We also give sildenafil 50mg on demand and educate how to take this drug. His total testosterone level showed 3,65 ng/mL: still in the normal laboratory range but within lower normal limit. We asked the patient to choose between evaluation the free testosterone level or directly given testosterone replacement therapy (TRT). Patient chose to be given TRT directly. He came for control in after 3 weeks. He said that he feels healthier, stronger, and more energetic to do his daily activities. The response of TRT in his erection is also good. NPT was started since the injection, and there is an increase in EHS score (EHS 2). He still had not any sexual penetration because he understands that his condition needs time to resolve. He started to modify his lifestyle by reduce his smoking and starts exercise regularly.

DISCUSSION
Several hormones are influenced by aging. Some hormones are increased, some constant, and some hormones are decreased. Most of hormone level in the elderly is decreased. Luteinizing Hormones (LH) and Follicle Stimulating Hormones (FSH) are increased in the elderly; but LH and FSH just increased at a very low level. Hormones which levels remain constant are Cortisol, Estradiol, Estron, and Dihydrotestosterone (DHT). Growth Hormones (GH), Insulin-like Growth Factor-1 (IGF-1), Dehydroepiandrosterone (DHEA), Melatonin, Thyroid Hormones, Thyroid Stimulating Hormones (TSH), Prolactin, and Testosterone are decreased. Total testosterone and free testosterone are both decreased. In the human circulation, testosterone is bound to protein, specifically Sex Hormone Binding Globulin (SHBG). In elderly, SHBG level are increased. In certain conditions such as hyperthyroidism, taking antiepileptic drugs, estrogen application, and hepatitis, SHBG level are increased and thereby increased testosterone concentration in serum. This condition occurs without an increase in biologically active free testosterone. 1 Testosterone is the main sex steroid produced by Leydig cells with a secretion rate of 7 mg/day. Adrenal also produced testosterone; about 5% of total testosterone was produced here. In plasma, testosterone is bound to SHBG, albumin and circulates freely. The Hypothalamic-Pituitary-Testicular axis Laboratory Examination is the main mechanism controlling the production of testosterone. Gonadotropin-Releasing Hormone (GnRH) secreted by the hypothalamus, will stimulate the pituitary to release LH, which later will stimulate the testis to produce testosterone. 4 Testosterone plays a major role in males. It is responsible for the development of primary sexual development in fetus, regulating secondary sexual male characteristics and skeletal muscle growth. 5 Testosterone is also important in regulating male sexual function; it is involved in every step of male sexual response. Impaired of sexual desire, morning erections, and erectile dysfunction (ED) is tightly related to low level of testosterone. 6 In the circulation, most of testosterone is bound to plasma proteins such as SHBG and albumin. Only a small amount of free testosterone is circulated. This free testosterone acts primarily at the androgen-dependent tissues, including seminal vesicles, muscle, bone, and prostate gland. Testosterone is converted to DHT by the enzyme 5-alpha-reductase to acts at the cellular level. Both testosterone and DHT bind to specific androgen receptor and regulate protein expression. 5 There were three factors that may cause the changes in serum testosterone levels in elderly. First, the incompetence of the feedback mechanism of Hypothalamus-Pituitary-Gonadal (HPG) axis in the elderly, because testosterone level is regulated by HPG axis. Second, the decreasing number and spare capacity of the Leydig cells. This is marked by less increase in serum testosterone after stimulation with HCG. Third, the increase in SHBG. In younger age, the increasing level of SHBG is followed by the increasing level of testosterone. In elderly, the increasing level of testosterone is not happened because the insufficiency and incompetence of HPG axis. 1 SHBG is a glycoprotein produced by hepatocytes. It is released into circulation as a homodimer of identical subunits, containing a single steroid-binding site for active androgens. 7 When discussing testosterone level in elderly, it is important to mention and discuss the free testosterone. As the smallest fraction of testosterone found in circulation, it is not routinely checked in Indonesia. There were several methods that can be used in estimating the level of free testosterone. Nanjee-Wheeler equation (regression analysis of free testosterone calculated by the gel filtration method), Sodergard equation (based on law of mass action; including albumin in its equation), Vermeulen equation (based on law of mass action) and Ly and Handelsman equation (ultrafiltration). Study by Ho CK, et al analyze and compare the level of free testosterone counted by each equation. The result is that mean bias is quite high between these equations, ranging from 5.8% to 56%. Free testosterone can also be estimated using Free Androgen Index (FAI) equation, using total testosterone and SHBG. But study found that FAI is poorly correlated with free testosterone levels, showing that the free testosterone level is overly estimated in the condition when SHBG levels are low. So, it is not recommended to be routinely used in daily practice. 8 We applied this theory into our patient. Actually, we can estimate the free testosterone level in our patients by evaluating SHBG and albumin level, since free testosterone is not routinely checked in our hospital. But as FAI and other equation have a high percentage of bias, we did not recommend this to our patient.

Hb
Late Onset Hypogonadism is a term first described by International Society for the Study of the Aging Male (ISSAM) in 2002. It is clinically and biochemically defined as a disease associated with advancing age, characterized by symptoms and a deficiency in serum testosterone. 2 There are several symptoms that are associated with low testosterone levels and divided into more-specific symptoms, lessspecific symptoms, and signs. More-specific symptoms of LOH are decreased libido, erectile dysfunction, and decreased frequency of morning erection. Less specific symptoms include decreased energy and motivation changes in mood, impaired memory, inability to concentrate, sleep disturbances, and hot flushes. Signs of LOH are decreased body/facial hair, central obesity, decreased testicular volume, decreased muscle mass, increase body fat, gynecomastia, and osteoporosis. 9 There are theories stated by Zitzman et al. in 2006 about the level of total testosterone and sign and symptoms of LOH. At first, the elderly will have their libido and vigor loss, followed by obesity. Later on, the symptoms will progress into feeling depressed, sleep disturbance, and lack of concentration. At its lowest level, symptoms such as hot flushes and erectile dysfunction will occur. 1 But this theory is not the same with patients we found in our Andrology clinic, since sign and symptoms of LOH in certain level of total testosterone varies between individual. To diagnose LOH clinically, one tool that is routinely used in daily practice is the Saint Louis University Androgen Deficiency in the Aging Male (ADAM) questionnaire. This questionnaire includes 10 questions. The test considered positive if answers are "Yes" to question 1, 7 or any 3 other questions. Question number 1 is "Do you have a decrease in libido -(sex drive)?" while question number 7 is "Are your erection less strong?". 10 These 2 questions are theoretically very related to LOH, as mentioned in the theory before. But one note should be carefully considered in deciding based on the results of this questionnaire. A study by Bernie,et al. 11 ) in 2014 showed that even though ADAM's questionnaire has a high sensitivity (83,3-97%), it has quite low specificity (19,7-36,6%). It means that there is a high possibility of false positives in identifying patients with LOH. So it is important for clinicians to always check and evaluate testosterone levels in patients with positive ADAM's questionnaire before initiating treatment in patients with LOH.
As mentioned, testosterone levels should be routinely checked in patients suspected of LOH based on ADAM's questionnaire. At first, testosterone level is measured using immunoassays method as it is fast, cheap, and reliable. Now the gold standard in evaluating testosterone is by mass spectrometry method. 12 Low testosterone levels should be diagnosed based on two examinations of blood samples taken at different times and under the same conditions. It should be noted that the blood samples should be taken before 10.00 AM, as it is related to the circadian rhythm of testosterone level in plasma. 13 Next question is how low is low enough to be given TRT in patients with LOH. A study by Park, et al 14 combined several cutoff values for total and free testosterone taken from other studies. ISSAM in 2015 stated that the cutoff value of total testosterone is <350ng/dL (12 nmol/L) and free testosterone is <65 pg/mL. the cutoff values of total testosterone and free testosterone stated by the Endocrine Society in 2018 are <300ng/dL and <5ng/dL respectively. Several Andrology and Sexual society also stated a different cutoff value. ISSM and Nieschlag textbook 1 cutoff values for total testosterone is the same with ISSAM (<350 ng/dL pr 12 nmol/L) and AUA cutoff values for total testosterone is same with Endocrine Society (<300 ng/dL). EAU cutoff value for total testosterone is slightly higher, 12,1 nmol/L. 13 Winters and Huhtaniemi in his book "Male Hypogonadism: Basic, Clinical and Therapeutic Principles" stated that TRT should be initiated if the repeat morning total testosterone level <350 ng/dL and/or the serum free of bioavailable testosterone are below the normal laboratory reference. 7 In Indonesia or Asia, there is still no specific cutoff values of low total testosterone. One study assessing the level and total free testosterone when the signs and symptoms of andropause appeared. Study by Pangkahila, W. in 2016 found that the level of total and free testosterone in Indonesia when symptoms of LOH appeared is still in normal range and higher compared to Caucasian population. The mean total testosterone level in patients with LOH that was diagnosed clinically in this study is 475.73 ± 133,32 ng/dL and mean free testosterone level is 10.44 ± 2.90 pg/dL. This higher level of total and free testosterone in this population may be caused by higher susceptibility compared to Caucasian. 15 So, the conclusion about how low is low enough to be given TRT is based on physician's perception. The question at which testosterone levels substitutions initiated has been determined by the physician's perception of hypogonadism than by the patients complain. Various cut off values and guideline has been stated above, but at the end the physician's perception of hypogonadism is the main reason and consideration about giving TRT. 1 Testosterone replacement therapy are first discovered in 1940s with testosterone implants as the agent. Up until now, several route of administration of TRT has been found, such as intramuscular (IM) injections, oral, transdermal, trans buccal and intranasal. There are several reported effects of TRT given. Reported benefits are increasing positive mood, sexual desire, muscle strength, lean body mass , bone mineral density, hemoglobin levels and decreasing body fat and fat mass. However, it should be noted that TRT also has a negative impact. Reported TRT risks known are increase PSA, acne or oily skin, testicular atrophy, gynecomastia, polycythemia, and sleep apnea. 3 The only two absolute contraindication or TRT are carcinoma prostate and carcinoma mammae. Relative contraindications are PSA level >4 ng/mL or > 3ng/mL in patients with high risk (African or family history of prostate cancer), hematocrit >50%, lower urinary tract symptoms (LUTS) caused by Benign Prostate Hyperplasia (BPH), uncontrolled or severe congestive heart failure. 1,12 Before given TRT, several things need to be settled. The most important thing is that we should understand the pharmacokinetics of the testosterone given to our patients. 1 TRT cannot be given in patients who still want to preserve his fertility function. Hemoglobin and hematocrit should be checked and patients should be well informed about the risk of polycythemia. PSA level should be measured in patients aged 40 and above, if possible, should be followed by digital rectal examination. If PSA level >4 ng/mL and nodule/irregularity was found in DRE, a proper and holistic follow up by urologist is needed. Complete blood count, lipid profile and liver function test are recommended to be checked. 12,16 After given TRT several psychic and sexual parameters should be evaluated, such as mood, libido, erections, sexual activity, body weight and proportion, muscle mass and strength, sebum production, etc. Laboratory parameters that can be evaluated are serum testosterone, gonadotropins, estradiol, liver enzyme, lipid levels, HbA1c, etc. Ejaculate volume, prostate size and PSA can also be evaluated in patients given TRT. The most important factor in evaluating TRT are as follows. First, it is important to know the pharmacokinetics of testosterone given. Second serum testosterone level should be measured directly before TRT is given to adjust the dosage and duration of TRT. If gynecomastia was found, estradiol level should be checked, lowering the dosage or change the route of administration. Liver function test should be measured every year even though the TRT given is not hepatotoxic. PSA level should measure every 3-6 months and every year thereafter; >4 ng/mL or increase >0,4 ng/mL compared to PSA level before is the alert for the evaluation of TRT and prostate problem. 1

CONCLUSIONS
Clinician should understand the physiologic hormonal changes in elderly. Total and free testosterone is decreased in this population. There are several specific symptoms related to hypogonadism, most importantly are decreased sexual desire, erectile dysfunction, and decreased frequency of morning erections. After diagnosing LOH clinically by using the ADAM questionnaire, it is important to evaluate the total or free testosterone level in plasma. Several consensuses stating different cut-off values. But in the end, at which testosterone levels substitution is initiated has been determined by the physician's perception of hypogonadism than by the patient's complaint. Various cut-off values and guidelines have been stated above, but the physician's perception of hypogonadism is the main reason and consideration for giving TRT. Choosing a different route of TRT administration is needed; pharmacokinetics needs to be understood. Evaluating TRT given is important to maximize the treatment's outcome. Somatic and laboratory parameters should be periodically evaluated.