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22. Treatment of Adult Male Hormonal Disorders
Keywords
Low testosteroneTestosterone deficiencyEstradiolProlactinIntroduction
Traditionally, testosterone has been the most important hormone for the practicing urologist to have familiarity with. Although a cursory understanding of testosterone regulating mechanisms is sufficient for most, those that treat patients regularly for conditions such as testosterone deficiency syndrome (TDS) and infertility require a more intimate knowledge of how testosterone is tightly regulated by the hypothalamic pituitary gonadal (HPG) axis. The HPG axis is comprised of the hypothalamus, the pituitary gland (comprised of anterior and posterior portions) and the testes. The hypothalamus secretes gonadotrophin releasing hormone (GnRH) in a pulsatile fashion, which enters the hypophyseal portal system in order to reach the anterior pituitary gland. This stimulates the anterior pituitary gland to secrete two hormones vital for reproduction, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The anterior pituitary gland also secretes adrenocorticotropin, growth hormone, prolactin, and thyroid-stimulating hormone (TSH). However, the roles of these hormones in reproduction and urologic diseases are poorly understood [1]. Thus, hormonal disorders a urologist may encounter and manage includes: testosterone deficiency syndrome, defects in FSH/LH production, elevated or low estradiol levels and prolactin production disorders.
Testosterone Deficiency Syndrome
Testosterone deficiency syndrome (TDS) can be characterized by a serologic laboratory value, generally total testosterone, below a certain pre-defined cutoff and symptoms such as decrease or loss of muscle strength, libido, memory, vitality, alterations in mood, and erectile dysfunction (ED). The epidemiology of this condition is difficult to address as rates vary widely among studies and populations depending on definitions used. Based on current evidence, however, one can confidently state that TDS becomes more prevalent as a man ages with longitudinal studies estimating a decline in total testosterone of 3.2–11 ng/dL per year and large cohort studies utilizing symptom surveys detecting an increase in TDS as men age [2, 3].
Unfortunately, there is no consensus as to how many TDS symptoms need to be present, and no practical set of objective measures outside of hormone laboratory testing, to classify a patient as having TDS. Even when utilizing total testosterone as an objective cutoff, it is notable that most professional societies that provide recommendations on the management of TDS use a lower limit of testosterone in the range of 300–350 ng/dL below which TDS can be diagnosed, with all requiring some kind of symptom assessment and at least two separate morning time measures of testosterone [4–6]. A cutoff of 300 ng/dL is further supported by a contemporary study utilizing a central lab at the Centers for Disease Control and Prevention (CDC) to harmonize testosterone values from several large cohort studies. This study revealed that 303 ng/dL was the average fifth percentile value among healthy non-obese patients between 19 and 39 years of age [7]. Occasionally, testosterone deficiency is diagnosed during a workup of primary or secondary male infertility and treatment of TDS varies greatly in this setting compared to aging related TDS [8]. Patients suffering from infertility with low testosterone typically require treatment with clomiphene citrate or human chorionic gonadotropin (hCG), two treatment modalities that will be discussed later in this chapter.
Before starting testosterone replacement (TRT) it is advisable to discuss the risks and benefits of testosterone replacement with patients and risk stratify them appropriately based on their risk factors. The U.S. Food and Drug Administration (FDA) lists the following contraindications to initiating TRT: breast cancer and known or suspected prostate cancer (although some would argue there are exceptions in some patients on active surveillance for low risk prostate cancer). Beyond this, however, it can be difficult to assess who is at greater risk of adverse events particularly since the risk profile of testosterone is yet to be satisfactorily defined. Addressing the undefined effect of testosterone as it relates to prostate cancer risk while on TRT, it is prudent to measure prostatic specific antigen (PSA) in patients over 40 years of age who are considering TRT given a man on TRT may theoretically have an increased risk of developing prostate cancer [9]. Since TRT is associated with polycythemia and increases in estradiol, a baseline complete blood count or hematocrit level along with a baseline estradiol is warranted. An assessment of pituitary gland function is also recommended by obtaining a baseline prolactin and LH. Occasionally, medically modifiable conditions such as a prolactin secreting prolactinoma may be detected [10]. A cardiovascular risk factor assessment is also necessary before considering TRT. A history of a prior stroke, myocardial infarction or thrombotic event should alert the urologist to at least relay the possible increased risk of stroke and cardiac events in those that use exogenous testosterone, particularly since the United States Food and Drug Administration (FDA) provides explicit warnings regarding a possible risk of adverse events in patients at increased risk of these conditions. This warning stems from studies, some of which are controversial in methodology and degree of clinical impact, linking the use of testosterone products to stroke, cardiac events, and death [11–13]. Men suffering from obstructive sleep apnea and lower urinary tract symptoms attributed to benign prostatic hypertrophy (BPH) should also be warned of possible aggravation in their symptoms while on TRT. However, contemporary data points to little if any clinically discernible worsening of these conditions on TRT [14–16]. Finally, regardless of patient age, a practitioner should always relay the fact that testosterone replacement can lead to infertility by inhibiting FSH/LH production through negative feedback mechanisms, with a subsequent drastic decline in spermatogenesis [17].
Treatment of TDS
Testosterone Replacement Options
Major available formulations | Dosing | Advantages | Disadvantages | Monitoring | |
|---|---|---|---|---|---|
“Sperm Unsafe” | |||||
Short Acting Injectables | Testosterone cypionate, Testosterone enanthate | 50–400 mg administered every one to four weeks | Weekly or longer dosing. Less variability in absorption. | “Peak and valley” effect. Injection pain/reactions. Polycythemia more likely. | 4–6 weeks after initiation. Draw labs mid-cyle (e.g. 2–3 days if on weekly dosing). |
Long Acting Injectables | Testosterone Undecanoate (Aveed) | 750 mg IM initially and at 4 weeks, then 750 mg IM every 10 weeks | Less injections. After reaches steady-state, Testosterone levels are reliable. | Injection pain/reactions. Pulmonary oil microembolism. | End of dosing interval. |
Gels/Creams | Testim™ and AndroGel® | 40 to 100 mg to skin daily | Non-invasive. Less likely to lead to polycythemia. | Potential to transfer from skin to skin contact. Variance in absorption. Compliance. Rash. | At least 1 week after initiation, 2–8 h after administration. |
Patches | Androderm®. | Patches | Non-invasive. Less likely to lead to polycythemia. | Skin irritation in up to 1/3 of patients. Variance in absorption. | At least 1 week after initiation, 3–12 h after administration. |
Pellets | Testopel® | 6–14 pellets every 3–4 months | Compliance more likely. Reliable absorption. | Procedure site reactions: Infection, pellet extrusion, hematoma. | 4–6 weeks after administration to evaluate peak. Alternatively, can check at end of dosing interval. |
Potentially “Sperm Safe” | |||||
Intranasal | Natesto | 1 actuation (5.5 mg of testosterone) per nostril two or three times per day | Non-invasive. Possible preservation of sperm production. | Requires at least twice-a-day administration. Variable absorption levels. | At least 1 week after initiation. |
“Sperm Safe” | |||||
Clomiphene | 25–50 mg every other day | Non-invasive. Inexpensive. Preservation of sperm production. | Potential estrogenic side effects. Case reports of blood clots (intracranial). | Not established. Consider 2–6 weeks post initiation. | |
Human chorionic gonadotropin (hCG) | 2000 units every other day or BIW | Preservation of sperm production. | Expensive. May lead to decreased FSH (feedback). | Not established. Consider 2–6 weeks post initiation. | |
Anastrozole | 1 mg two times per week | Preservation of sperm production. Inexpensive. | Low estradiol levels (low libido, decreased bone mineral density). Only suitable as monotherapy for those with high estradiol/testosterone ratio. | Not established. Consider 2–6 weeks post initiation. | |
Short Acting Injections
Testosterone injection formulations are supplied in several depot forms with the active ingredient being a testosterone molecule with the addition of a carbon chain (ester). The size of the carbon chain determines the solubility and hence the half-life of the testosterone molecule. Two of the most common formulations available for intramuscular (IM) injection are testosterone cypionate (TC) and enanthate (TE). These formulations have a half-life of 8–9 days and are typically given at weekly or every-other-week regimens. It should be noted that the FDA recommended doses are 50–400 mg administered every 2–4 weeks [18]. Every-other-week dosing may lead to high peaks and low valleys at the end of the administration schedule making it hard to find an ideal dose and potentially lead to adverse side effects such as polycythemia or mood disturbances [19]. For example, in one study that administered TC 200 mg IM in 11 hypogonadal men the mean peak testosterone was supratherapeutic (1112 ± 297 ng/dL) and occurred between days 4 and 5 post-injection. By day 14 the mean testosterone was noted to be around 400 ng/dL suggesting most men were therapeutic throughout most of the 2 weeks. However, these large fluctuations and exposure to supraphysiologic testosterone over at least part of the 2-week period illustrate the less than ideal kinetics of every-other-week testosterone dosing [20]. Thus, to minimize the “peak and valley” effect noted in every-other-week dosing patterns, patient self-administered testosterone IM at weekly intervals is preferred in our practice. These injectable testosterone formulations may be started at 100 mg weekly (e.g. 0.5 mL of a 200 mg/mL solution) delivered through the IM route. In an attempt to further blunt the peak and valley effect, subcutaneous administration of lower amounts of testosterone two times per week has also been studied in small patient populations but has not been evaluated by the FDA [21]. The benefits of testosterone delivered by injection include attainment of reliable levels of testosterone compared to topical formulations. Acute side effects unique to the injectable form of testosterone include injection site reactions and pain, as well as allergic reactions to the oils and preservatives used in testosterone injection formulations.
Long Acting Injections
With a half-life of about 21 days, Testosterone undecanoate (TU) is a much longer acting formulation of injectable testosterone compared to TE and TC. The typical FDA sanctioned starting dose is 750 mg of TU injected IM initially, then at week 4, and then every 10 weeks thereafter. Pharmacokinetic studies show that TU typically leads to peak testosterone levels at 7 days after each injection and steady state, where testosterone levels remain above the therapeutic range throughout the treatment period, is typically reached after the third injection administered at week 14 [22]. A successful user of TU should therefore only require about 5–6 injections per year compared to 26 or more injections in patients that use TE or TC as their injectable of choice for TRT. However, given it takes at least three consecutive injections to get to steady therapeutic levels, poor compliance or delay of even one injection can lead to testosterone levels below therapeutic levels for a portion of the treatment period. Similar to other injectable formulations TU has the side effect of pain at the injection site, which can be more prominent given the injection of 3 mL of product is required (compared to 0.5–1 mL for TE/TC). Although rare, pulmonary oil microembolism and anaphylaxis have been reported with TU use.
Transdermal Testosterone Delivery
Approximately two-thirds of men on TRT use gel or cream preparations. Although there are several testosterone gel/cream preparations available, including compounding pharmacy products, the two most common formulations encountered in the clinic setting are Testim™ and AndroGel® . These formulations typically suspend testosterone in a hydroalcoholic gel (with different types of emollients) that is rapidly absorbed into the stratum corneum of the skin which serves as a time release reservoir [23]. Typical administration sites include the shoulders, upper arms, and abdomen. Typical starting doses range from 40 to 100 mg of delivered testosterone daily. From pharmacokinetic studies it is evident that levels tend to increase over 18–24 h after administration but individual measurements tend to vary significantly during the course of administration [23, 24]. Steady state levels tend to be reached by the third day of administration. The most obvious benefits of gels/creams are the non-invasive nature of using gels/creams and the ease of portability as no needles are necessary. The most common side effects of testosterone topicals include skin irritation, poor compliance and inability to reach physiologic testosterone levels leading to no chance of symptom improvement and subsequent discontinuation. One should also counsel patients on the potential to transfer testosterone from skin to skin contact.
A testosterone delivery system in the form a daily patch is also available and marketed as Androderm® . Pharmacokinetically, this product is advertised to mimic the normal circadian variation of testosterone as it is applied at night, leading to peak testosterone levels in the morning. Long term use data shows that patients reach average testosterone levels around 412–498 ng/dL. However, average trough testosterone levels tend to be well below 300 ng/dL [25]. Furthermore, the use of patches is plagued by patient discontinuation due to skin irritation which has been reported in up to 1/3 of patients who use patches [26].
Intra-Nasal Testosterone
One of the newer forms of TRT available on the market is intranasal testosterone gel (Natesto™). The intranasal form of administration takes advantage of the high permeability offered by nasal mucosa. The bioavailability of testosterone through this route is further enhanced by the fact the drug is not subject to first pass metabolism. The typical starting dose is 1 actuation (5.5 mg of testosterone) per nostril two or three times per day. Pharmacokinetic studies in hypogonadal men shows an average testosterone of 386 ng/dL when used three times per day with a range of 200–935 ng/dL during an administration period [27]. Interestingly, in preliminary results from a phase IV clinical trial, testosterone delivery in the form of Natesto seems to limit negative effects on LH and FSH production to a degree that preserves sperm parameters such as total motile sperm count after 3 and 6 months of use [28]. Thus, intra-nasal testosterone may soon turn out to be a reasonable choice for TRT in patients attempting to maintain their fertility potential during TRT, and at the same time would prefer to use an FDA approved TRT medication that may be covered by insurance while avoiding off label use of medications such as human chorionic gonadotropin (hCG) or clomiphene citrate.
Implantable Testosterone Pellets
Another long-acting testosterone replacement option approved by the FDA is the implantable testosterone pellet marketed as Testopel® (75 mg testosterone per pellet). These pellets are typically inserted in an office setting in the subcutaneous tissue in the upper buttocks or lower back through a small incision under local anesthesia. One retrospective multi-institutional study on the pharmacokinetics of Testopel® showed that regardless of the number of pellets implanted, mean peak testosterone levels occurred at 4 weeks post implantation. Mean total testosterone tended to be maintained above 300 ng/dL for 4 months regardless of pellet number (range 6–10). However, higher pellet numbers were associated with levels closer to mid-normal of testosterone throughout the entire treatment period of three months [29]. Determining how many pellets to insert and how often (every 3–4 months) depends on patient circumstances, individual testosterone levels during pellet therapy, and possibly BMI with more pellets likely needed for those with a higher BMI [30]. Adverse short-term events typical of testosterone pellet administration includes pain/discomfort at insertion site, hematoma, infection, skin rash and pellet extrusion. The rate of all adverse events outside of pain/discomfort are reported at <1%. The benefit of testosterone pellets lies in the fact the patient would need only four administrations of testosterone per year.
Human Chorionic Gonadotropin (hCG)
Most of a man’s endogenous testosterone is produced by Leydig cells in the testicle as a result of direct stimulation by LH, which is controlled by the pulsatile secretion of GnRH. Human chorionic gonadotropin (hCG), which has a pharmacological action similar to LH, has the capacity to be used to stimulate endogenous testosterone production. Most of what we know regarding the ability to treat patients with TDS with hCG comes from treatment of patients with hypogonadotropic hypogonadism. In these patients, hCG has been shown to be able to stimulate spermatogenesis as a direct result of increasing intra-testicular testosterone [31]. Early studies in men with normal testosterone levels revealed that a 1500 IU dose of hCG can increase testosterone levels by about 2×, on average, 48 h after administration [32]. A more contemporary study on patients with TDS suggests hCG can be as effective as other forms of TRT in reaching testosterone levels with the difference being hCG does not seem to have a negative effect on semen parameters or testicular volume [33]. There are no standard doses or intervals for hCG administration in TDS treatment. Low dose hCG divided into several doses (300 IU over 5 days) may be more effective at producing an optimal testosterone to estradiol ratio compared to a single larger dose (1500 IU × 1 dose) [32] Another study shows that hCG induces a biphasic response in testosterone production resulting in a peak at 2–4 h and a higher one at 48–72 h after one administration of hCG [34] This would indicate that every third or fourth day dosing is ideal. In our practice we typically start with 2000 IU of hCG administered in an intramuscular or subcutaneous fashion two times per week. Outside of adverse reactions related to injection and higher testosterone levels (e.g. polycythemia), no unique side effect profile has been attributed to hCG administration. However, no large prospective studies exist evaluating the efficacy of hCG for the treatment of TDS to glean a side effect profile from, and thus, it is used off-label (not FDA approved) for this purpose.
Clomiphene Citrate
For most andrologists , clomiphene citrate (Clomid) serves as an option in the treatment of TDS, although it is used off-label for this purpose as well. Clomiphene is a selective estrogen receptor modulator (SERM) that is found in a racemic mixture of two isoforms (enclomiphene and zuclomiphene) with both antagonism and agonist activities. It works to increase testosterone by competitively binding to estrogen receptors in the hypothalamus and pituitary gland decreasing the negative feedback estrogen provides. As a result, LH production by the pituitary increases, eventually leading to an increase in testosterone. Given clomiphene’s potential to preserve LH and FSH production, and as a result spermatogenesis, it has mostly been studied in younger men (<50 yo) for its potential to replace testosterone. One study in 86 healthy young men (mean 29 years of age) taking clomiphene at either 25 mg or 50 mg every other day showed an increase in total testosterone from a mean of 192 to 485 ng/dL after 6 months of treatment. Interestingly this study did not reveal any major side effects and no patient ceased treatment because of adverse reactions [35]. The optimal dosing of clomiphene citrate (CC) is patient specific, however, taking into account clomiphene’s half-life is estimated to be 10–14 days, we prefer to start at 25 mg two times per week and titrate up as needed to achieve desired testosterone levels. Side effects attributed to clomiphene include headaches, gastrointestinal symptoms, hot flushes, nausea, dizziness, visual disturbance, weight gain and fluid retention. Rare cases of central retinal vein occlusion in a man with factor V Leiden and a case of intracranial venous thrombosis presenting as a severe headache have been reported [36]. Theoretically, the enclomiphene isomer of clomiphene (Androxal) may have less chances of precipitating these side effects given it has mostly estradiol antagonist properties. Although it has been shown to reliably increase testosterone levels in those with TDS, enclomiphene has not received FDA approval [37].
Oral Testosterone Formulations
Oral formulations of TU are currently not available in the United States and as of January 2018 have not been approved by an FDA advisory panel due insufficient data on short and long term risks. Oral TU is available in Europe and some parts of Asia however and is marketed as Andriol® Testocaps® . Most studies on oral TU date back to the 1970–1980 and show that oral TU typically only modestly increases testosterone levels with difficulty achieving therapeutic levels in most study participants [38].
Monitoring
Checking testosterone levels regularly in those on testosterone replacement is advocated by most professional medical society guidelines. Typically, a testosterone level is drawn at the 4 week to 3 month mark for an initial measurement that facilitates titration. Table 22.1 lists typical time-points in an administration cycle as to when testosterone should be drawn to aid in testosterone titration.
The risk of polycythemia from TRT is troublesome due to a potential to exacerbate vascular diseases (coronary, peripheral, cerebral). Injections are associated with the greatest risk of erythrocytosis compared to topical formulations [39]. In one study, testosterone enanthate given at weekly doses of 25–600 mg lead to hemoglobin and hematocrit increases in a linear, dose-dependent fashion in both young and older men [40]. Thus, routine monitoring of hemoglobin/hematocrit is strongly advised particularly with injectable regimens. To simplify regimens it is typically recommended that a hematocrit be checked every time a testosterone level is checked unless it is to monitor response to a phlebotomy session. Strategies in patients who develop polycythemia include decreasing the testosterone dose or prescribing regular phlebotomy sessions.
Hepatotoxicity is currently thought to be limited to steroids which are designed for oral administration [41]. Unless an oral testosterone formulation is prescribed, liver function monitoring is not routinely recommended for patients receiving testosterone. Similarly, routine monitoring of lipid profiles is not strongly recommended. This is supported by studies that do not show any discernible changes in cholesterol levels, outside of a possible mild decrease in HDL, even with supraphysiologic testosterone levels [42, 43].
As previously alluded to, although evidence linking testosterone replacement with a higher risk of prostate cancer development is weak, PSA and DRE checks at 3–12 month intervals are supported by most society guidelines on testosterone replacement [5, 44].
Lastly, while someone is on testosterone replacement therapy, particularly early on, it is important to monitor symptoms to ensure the patient is deriving at least subjective improvement. Questionnaires such as the Androgen Deficiency in the Aging Male (ADAM) questionnaire may prove useful for this purpose [45]. It should be emphasized that the goal should be to achieve physiologic levels of testosterone and only continue therapy if patients do experience improvement in symptoms attributed to low testosterone.
Estradiol
The importance of normal estradiol levels in men is exemplified by studies conducted on men receiving exogenous testosterone with aromatase inhibitors, as well as congenital cases of aromatase deficiency. In one unique study assessing the role of estradiol in men researchers used goserelin acetate to suppress endogenous testosterone and estradiol production. Men were then treated with exogenous testosterone and randomly assigned to administration of aromatase inhibitors (AI) to prevent the conversion of androgens to estradiol by blocking the action of the enzyme aromatase. Interestingly, significant estradiol deficiency in those treated with AI lead to a decline in sexual desire and more undesirable fat distribution [46]. More extreme cases of low estradiol levels can be found in patients with aromatase deficiency. These men tend to develop osteopenia, above-average height due to delay in fusion of the epiphyses, abnormal lipid profiles and infertility. Interestingly, treatment of these patients with exogenous estradiol can lead to improvement in some of these abnormalities [47]. Given the association of low estradiol with osteopenia, measurement of bone mineral density may be needed only in those with low estradiol levels. On the other hand, cases of aromatase excess usually present as men with gynecomastia, accelerated growth and premature bone maturation [48]. Anastrozole (Arimidex) represents a common AI used by andrologists. This medication is typically used to decrease iatrogenic excess in estradiol that may accompany testosterone replacement. In men using anastrozole to treat an iatrogenic excess of estradiol a typical starting dose is 1 mg every other day given its half-life of 50 hours. Although difficult to define a normal range for men, a range of 20–60 pg/mL is typically targeted in men on TRT. Anastrozole and other AIs have also been studied as monotherapy in the treatment of TDS, especially in patients with a low testosterone to estradiol ratio. Typically, AI therapy tends to increase testosterone levels to well within the therapeutic range (>350 ng/dL) consistently. However, estradiol levels fall to levels that may precipitate symptoms such as loss of libido and impact bone mineral density in a negative manner [49]. Thus, AIs are rarely used as monotherapy for TDS and it should be noted that AIs are not FDA approved for this purpose.
Prolactin
It is known that an excess of prolactin, typically as a result of a productive prolactin secreting adenoma in the pituitary gland, can contribute to a decline in GnRH secretion and thus a subsequent decrease in LH production. Without adequate stimulation, Leydig cells in the testicle stop producing adequate amounts of testosterone leading to TDS. On the other hand, low prolactin levels have also been associated with derangements in the following areas: metabolic, psychological, erectile and ejaculatory [50, 51]. Currently, there is no practical way to supplement or increase prolactin levels and, given the weak evidence that hypoprolactinemia leads to clinically relevant disease, it is questionable how much weight should be put on an isolated finding of hypoprolactinemia . Hyperprolactinemia, however, is a well established condition. The first decision a clinician has to make is when to check prolactin. Professional society guidelines generally advise checking prolactin in any patient diagnosed with TDS, particularly if LH is low or normal. Some studies further suggest the need for a pituitary MRI in patients with a testosterone of <150 ng/dL and low/normal LH levels regardless of prolactin levels [39]. However, a more recent study suggests one is unlikely to detect significant pituitary findings until prolactin levels are at least two times above normal levels [52]. If a pituitary abnormality is found, an endocrinology referral is warranted unless the urologist is experienced in managing prolactinomas.
Conclusion
Adult male hormonal disorders typically encountered by urologists involve the hormones testosterone, estradiol and prolactin. Unfortunately, there are no definitive recommendations on the symptoms and laboratory value ranges attributed to derangements in these hormones and the practitioner should alert the patient of the ambiguity of what defines conditions such as testosterone deficiency. It should be emphasized that close laboratory and symptom monitoring is necessary to avoid potential side effects in patients being treated for these hormonal derangements. A guide on the evaluation, treatment, and monitoring of patients with symptoms and laboratory values consistent with abnormal testosterone, estradiol, and prolactin levels are provided in this chapter. However, this should not be interpreted as a delineation of strict protocols and treatment should always be individualized to the patient and his co-morbid conditions and symptoms.
