Treatment of estrogen levels in the management of hypogonadism: An anonymous survey of ISSM members.

Abstract

Objective:

To assess the variability in management of estrogen levels in men treated with testosterone therapy (TTh). With the significant increase in the last two decades in the treatment of hypogonadism and the use of TTh, detailed guidelines for the management of estrogen levels are necessary. (1)

Materials and Methods:

An anonymous survey was electronically distributed to the membership of the International Society for Sexual Medicine including questions on demographics, symptoms, and their approach to management of estrogen in patients on TTh. Chi-square test was used to determine associations.

Results:

The response rate was 22.5% (489/2168). 62.4% indicated that they check serum estrogen at initial evaluation, but only 54.7% monitor levels in patients on TTh (p=0.02). Fellowship-trained and North American respondents were more likely to monitor patients(p<0.05). 69.4%, 47.7%, and 14.4% of respondents prescribe anti-estrogenic medications in symptomatic patients with elevated estrogen levels, for asymptomatic elevated estrogen levels, and prophylactically respectively. Academic respondents were more likely to prescribe an anti-estrogen medication to symptomatic patients and prophylactically(p<0.05). Anastrozole was the most common medication prescribed for symptomatic hyperestrogenemia (62.3%), but starting doses varied significantly, from 1mg weekly to 1mg daily.

Conclusions:

Approximately 50% of practitioners treating men with TTh monitor estrogen levels. Symptoms play a role in prescribing patterns and significant variability in aromatase inhibitors regimens exists. Increased monitoring of estrogen levels in men on TTh will facilitate an understanding of the symptoms, effects of high and low estrogen levels, and aid in standardization of research and therapy.

Introduction

Testosterone is an important hormone in male development, as well as in reproductive and sexual function. Hypogonadism in adult men is defined as a clinical and biochemical syndrome associated with low levels of testosterone due to testicular or hypothalamic-pituitary dysfunction and symptoms, including sexual dysfunction, decreased libido, and decreased energy, among others. (1, 2) Hypogonadism can affect overall mortality, cardiovascular health, and cause sexual and musculoskeletal dysfunction in men, leading to a decrease in quality of life.(3–6)

The use of testosterone therapy (TTh) has increased 1.8 to 4-fold over the last 2 decades based on studies evaluating prescription trends. (7) The treatment for hypogonadism can often involve a combination of TTh, lifestyle modification, and optimization of comorbidities to augment physiological testosterone levels. (8, 9) TTh is available in a number of formulations including intramuscular injections, subcutaneous pellet implants, controlled-release buccal formulations, nasal application, and transdermal gels/patches, each with advantages and disadvantages. The risks of TTh include erythrocytosis, hyperestrogenemia, gynecomastia, suppression of endogenous testicular function, male infertility, and worsening sleep apnea, among others. (2, 10–12) Though male hormone management has evolved into a complicated subspecialty, requiring specialized knowledge, a diverse set of healthcare practitioners encounter and manage this condition, including primary care providers, endocrinologists, urologists, and physician extenders, and treatment regimens are highly variable.

Increased serum testosterone levels may result in elevated serum estradiol as a result of aromatization. In the absence of routine monitoring of estradiol levels, we are reliant on clinical symptoms for diagnosing hyperestrogenemia. Historically considered a “female hormone”,we have limited data on the role of rising estradiol levels in the face of testosterone replacement for hypogonadism. Though the American Urological Association (AUA) guidelines mention hyperestrogenemia as a risk of TTh, and mention the use of aromatase inhibitors (AI’s) as a treatment option for hyperestrogenemia, no further guidelines regarding management of estrogen levels are provided.(13) Guidelines regarding its management from other major societiessuch as the European Association of Urology (EAU) and the Endocrine Society are also lacking.(12, 18) We hypothesize that the lack of data and guidelines are likely leading to highly variable practice patterns. Here we aim to assess the variability in provider diagnosis and management of estrogen levels in men treated with TTh across the ISSM membership who manage hypogonadism.

Materials and Methods

A 28-question electronic survey was developed to anonymously assess demographic information and current practice patterns in the management of estrogen levels during TTh. (Supplementary Figure 1). An emphasis was placed on the monitoring and interpretation of estrogen levels and effects during treatment for hypogonadism, and the subsequent impact on treatment. Since this is a relatively novel topic, the survey was designed based on our own clinical practice and queries. The survey can be found in Appendix 1. This survey was then distributed to all 2,168 members of the International Society for Sexual Medicine (ISSM) using Survey Monkey (SurveyMonkey Inc, San Mateo, CA, USA). It was sent electronically three times between July and November 2018 and was kept open during this period. No incentives were used. All participants provided anonymous consent by clicking “Yes” on a consent page prior to being able to view and fill out the survey which was required to proceed to the remaining survey. The question asking for consent was the only required question. The study and survey were approved the by the Baylor College of Medicine Institutional Review Board. Subgroup-analyses to compare responses based on fellowship training, practice type, and region were also conducted to assess for variability in responses based on these factors. Descriptive analyses were performed, and Chi-square test used to determine associations between categorical variables. All statistical analyses were performed using SPSS v22 (IBM, NY).

Results

Of the 2,168 people who were sent the survey, 489 consented and completed the survey (response rate 22.5%). 330 surveys were completely completed while the other surveys had at least one missing piece of information. Total number of respondents for all questions have been provided explicitly in the result section and tablesto enhance transparency and accuracy of results. The majority of respondents (380/454, 83.7%) were private practitioners or attending physicians and 67.0% (304/454) had completed fellowships in andrology, sexual medicine, or male infertility. (Table 1) The majority of respondents (406/441, 92.1%) stated that from 0–40% of their practice included treating hypogonadal men using TTh. Injectable testosterone was commonly used in the treatment of hypogonadism, with 43.3% of respondents using injections for primary management of hypogonadism in >40% of patients. 62.4% (275/441) of respondents indicated that they check serum estrogen levels in their initial hypogonadal evaluation, while 54.7% (241/441) routinely monitor estrogen levels in patients on TTh (p=0.02). As shown in table 2, Fellowship- trained and North American respondents were more likely to monitor estrogen levels during initial and subsequent evaluations.

Table 1:

Respondent Demographics

Question	Responses, n (%)
Years in Practice
< 5 years	64 (14.1)
5 – 10 years	89 (19.6)
10 – 15 years	60 (13.2)
>15 years	241 (53.1)
Level of Training
Private Practitioner/Attending Physician	380 (83.7)
Resident / Fellow Physician	42 (9.3)
Advanced Practice Provider	32 (7.1)
Fellowship training
Yes	304 (67.0)
No	150 (33.0)
Practice Type
Private practice, not employed by hospital	173(38.1)
Private practice, employed by hospital	100 (22.0)
Academic	156 (34.4)
Employed by the government	25 (5.5)
Practice location
Urban	368 (81.1)
Suburban	71 (15.6)
Rural	15 (3.3)
Region
North America	201 (44.3)
Europe	92 (20.3)
Other	161 (35.5)
Practice Size
Solo	98 (21.6)
2 Urologists	40 (8.8)
3–5 Urologists	95 (20.9)
6–19 Urologists	101 (22.3)
11 or more Urologists	120 (26.4)
Specialty
Urology	360 (81.8)
Primary Care	20 (4.6)
Endocrinology	12 (2.7)
Other	48 (10.9)

Table 2:

Association of responses to fellowship training, practice type, and geography of respondents

Question		No fellowship	Fellowship	p-value	Private	Academic	p-value	NA	EU	Other	p-value
Do you routinely check serum estrogen levels in men suspected of having hypogonadism during your initial evaluation?	No	69	97	0.003	105	59	0.165	64	33	69	0.049
	Yes	77	198		157	117		134	57	84
Do you routinely monitor serum estrogen levels in hypogonadal patients on testosterone therapy?	No	80	120	0.005	123	75	0.372	74	40	86	0.002
	Yes	66	175		139	101		124	50	67
In hypogonadal men you treat with testosterone therapy, do you consider serum estrogen levels above the upper limit of normal an “abnormal” finding?	No	37	91	0.38	67	61	0.108	67	20	42	0.43
	Yes	70	139		128	81		104	44	61
In hypogonadal men you treat with testosterone therapy, do you consider serum estrogen levels below the lower limit of normal as an “abnormal” finding?	No	67	136	0.319	123	80	0.43	91	43	69	0.053
	Yes	40	103		80	62		83	23	37
In your hypogonadal patients on testosterone therapy who are found to have an abnormally elevated serum estrogen level on routine follow-up labs, would you prescribe an anti-estrogen medication?	No	53	108	0.742	89	72	0.339	57	43	61	0
	Yes	61	134		117	77		118	23	54
In your hypogonadal patients on testosterone therapy who are found to have an abnormally elevated serum estrogen level on routine follow-up labs and complain of clinical symptoms, would you prescribe an anti-estrogen medication?	No	20	57	0.28	56	21	0.006	13	25	39	0
	Yes	92	192		157	126		162	45	77
Do you routinely prescribe an anti-estrogen medication to your hypogonadal patients on testosterone therapy to prevent side effects of an elevated serum estrogen level?	No	121	230	0.172	216	134	0.021	154	78	119	0.058
	Yes	15	44		27	32		34	6	19
For anastrozole (Arimidex), which of the following is your preferred initial starting dose for a hypogonadal patient on testosterone therapy with a symptomatically elevated serum estrogen level?	1 mg PO daily	9	57	0.001	32	34	0.092	23	15	28	0
	1 mg PO three	20	45		32	33		45	8	12
	1 mg PO twice	25	43		35	33		47	8	13
	1 mg PO weekly	26	30		36	19		33	9	14
	Other	9	11		15	5		20	0	0
When prescribing an aromatase inhibitor, do you consider decreased bone mineral density over time as an associated risk of therapy?	No	27	52	0.787	46	33	0.796	45	11	23	0.363
	Yes	82	170		142	109		128	53	71
When prescribing an aromatase inhibitor, do you routinely monitor bone mineral density with DEXA scan or other modality during follow up?	No	62	141	0.468	117	85	0.377	120	31	52	0.017
	Yes	38	72		58	52		47	27	36
When prescribing an aromatase inhibitor, do you routinely monitor liver function tests during follow up?	No	39	80	0.886	64	54	0.571	88	7	24	0
	Yes	64	136		115	85		81	49	70
When prescribing an aromatase inhibitor, do you consider decreased bone mineral density over time as an associated risk of therapy?	No	27	52	0.787	46	33	0.796	45	11	23	0.363
	Yes	82	170		142	109		128	53	71
When prescribing an aromatase inhibitor, do you routinely monitor bone mineral density with DEXA scan or other modality during follow up?	No	62	141	0.468	117	85	0.377	120	31	52	0.017
	Yes	38	72		58	52		47	27	36
When prescribing an aromatase inhibitor, do you routinely monitor liver function tests during follow up?	No	39	80	0.886	64	54	0.571	88	7	24	0
	Yes	64	136		115	85		81	49	70

Respondents associated breast enlargement (290/425, 68.2%), nipple tenderness/sensitivity (277/425, 65.2%), low libido (186/425, 43.8%), fluid retention/edema (156/425, 36.7%), erectile dysfunction (128/425, 30.1%), moodiness/irritability (110/425, 25.9%), or “all of the above” (134/425, 31.5%), with elevated estrogen levels. The most common response associated with low serum estrogen levels was “none of these” (149/425, 35.1%) followed by low libido (121/425, 28.5%). A smaller number of respondents also associated moodiness/irritability (80/425, 18.8%), erectile dysfunction (68/425, 16.0%), joint pain/arthritis (67/425, 15.7%), breast enlargement (33/425, 7.8%), nipple tenderness (31/425, 7.3%), fluid retention or edema (26/425, 6.1%), or all of the above (16/425, 3.8%) with low serum estrogen levels.

Of the respondents, 69.4% (284/409) indicated that they would prescribe anti-estrogenic medications in symptomatic patients with elevated estrogen levels, while 47.7% (195/409) would prescribe it for asymptomatic patients with elevated estrogen levels. Additionally, 14.4% (59/410) would prescribe it prophylactically when a patient starts on TTh (p<0.0001).North American respondents and respondents associated with an academic practice were more likely to prescribe anti-estrogen medications as shown in table 2. 81% (324/401) of respondents would prescribe an AI to a hypogonadal patient on testosterone therapy with a symptomatically elevated serum estrogen level, while 24% (98/401) of respondents would consider a selective estrogen receptor modulator (SERM). Anastrozole was the most common medication prescribed for symptomatic hyperestrogenemia (250/401, 62.3%), but dosing regimens varied significantly, ranging from 1 mg PO weekly to 1 mg PO daily (Figure 1). Other medications that were specifically queried about included tamoxifen (98/401, 24.2%), letrozole (56/401, 14.0%), exemestane (18/401, 4.5%), while 3.3% (13/401) respondents selected “All of the above” and 20.1% (80/401) selected “None of the above” as a medication they would prescribe to a hypogonadal patient on TTh with a symptomatically elevated serum estrogen level. Though 63.5% (252/397) of respondents considered decreased bone mineral density (BMD) over time as an associated risk of AI therapy, only 27.6% (110/398) indicated that they routinely monitor patients’ bone densities. (p<0.0001). North American respondents were less likely to monitor their patients for these side effects as detailed in table 2.

Figure 1:

Preferred Initial dose of Anastrozole

Discussion

In this study, we sought to assess current practices in the management of estrogen levels in hypogonadal men on TTh. Injectable preparations are a commonly used route for testosterone supplementations. However, we did not specifically query our respondents regarding gels and pellets. Lowui costs, and less frequent dosing likely in part explains the popularity of injectable formulations, despite the discomfort of injection, potential irritation at injection site, and mood lability associated with injections.

Although respondents identified a number of symptoms typically associated with hyperestrogenemia, a number of respondents also believed that these symptoms are present irrespective of whether the patient has hypo- or hyperestrogenemia. Furthermore, several respondents indicated that men with hypoestrogenemia would be asymptomatic. A large number of respondents indicated that they would prescribe anti-estrogenic medications only for symptomatic patients, compared to asymptomatic men with elevated estrogen levels (284/409, 69.4% vs. 195/409, 47.7%). These responses show that the presence of symptoms drives the prescription of anti-estrogenic medications among a significant number of practitioners. While the presence of hyperestrogenemia symptoms may currently be the primary driver for the assessment of estrogen levels, symptoms might not necessarily be the exclusive reason to start therapy. The threshold for symptoms is variable between patients, further supporting the regular monitoring of estrogen levels. It is not uncommon for Estradiol levels to rise during TTh. (14) However, nearly 40% (166/441) of our respondents do not routinely assess estrogen levels either at baseline or in patients on therapy. This is similar to data in recent studies that highlight decreased follow-up to TTh, including a lack of post-treatment testosterone and pre- and post-treatment estrogen levels. (15–17) A large proportion of our respondents associated breast symptoms such as nipple tenderness (277/425, 65.6%) and breast enlargement (290/425, 68.1%) with an abnormally elevated estrogen level during treatment. Current AUA guidelines recommend serum estradiol measurement in testosterone deficient patients who present with breast symptoms or gynecomastia prior to the commencement of TTh and monitoring based on the appearance of breast symptoms during TTh.(13) However, the EAU currently has no explicitly stated guidelines regarding estrogen management. This might be contributing partially to some of the training-based and geography-based differences seen in our data. Both the EAU and the AUA guidelines recommend monitoring of BMD in men whose BMD was abnormal before initiation of TTh,(13, 18) However, very few of our respondents monitored BMD during AI use in which decreases in BMD are a known side effect. (19)

Studies assessing symptoms of estrogen imbalance in hypogonadism have shown its effect on BMDand subsequently on osteoporotic fractures, body mass and consequently on glucose metabolism, and on sexual function and spermatogenesis as well.(14, 20, 21) A growing number of studies evaluating estrogen modulators in the setting of hypogonadism have been conducted over the last decade, but these studies are limited by small highly-variable populations, lack of control groups, variable treatment strategies, and a lack of long term follow-up data affecting their generalizability.(22–25) Furthermore, these studies are often performed using different outcome measures including side effects, fertility, symptoms, and biochemical response making comparison complex. Despite the lack of high quality evidence, anti-estrogenic medications such as AI’s and SERM’s are commonly used off-label as an alternative to TTh in the treatment of hypogonadal patients desiring fertility, primarily to protect spermatogenesis from the inhibitory effect of testosterone via feedback from the hypothalamic-pituitary axis.(13, 26, 27) The evidence for use of these medications is even weaker when considered in the setting of patients on testosterone supplementation.

In our clinical experience, prophylactic aromatase inhibitor initiation pre-empts symptoms of hyperestrogenemia in patients on TTh. We traditionally begin anastrozole when patients start injectable TTh. However, very few respondents start AIs prophylactically, with majority starting these medications only if patients are symptomatic, regardless of estrogen levels. Regarding dosage, we prescribe 1 mg of anastrozole weekly for every 200 mg of testosterone taken weekly. Patients on TTh follow up in our clinic every three to four months, and an estrogen level is rechecked at every visit. Anastrozole dosing is increased if estrogen is above the normal range for males, and lowered if it is undetectable. In some patients, who are symptomatic while on anastrozole therapy, we consider using tamoxifen as needed in addition to modulate the effect of estrogen. There is limited evidence on using this approach and this is largely based on anecdotal evidence in our clinical practice and does not reflect current guidelines. In our experience, we have noted changes in libido at both low and high estrogen levels, and that keeping patients within the normal range yields the best results.

Our survey data show that there is significant variability in anti-estrogenic medications used, their dosage, and indications. This variable treatment highlights the need for additional evaluation of these parameters in order to design standardized treatment protocols that incorporate the appropriate starting point and dosing to minimize side effects of anti-estrogen therapy in men. Increased monitoring of estrogen levels and symptoms can provide us with objective measures to potentially help us better elucidate the effects of estrogen, develop optimal treatment protocols, and most importantly clinically impact our patients.

Our study has a number of limitations that are worth discussing. As in any other self-reported survey, recall bias is an inherent limitation. Our response rate was 22.5%; however, this is higher than other studies of this nature.(28, 29) Our survey was limited to members of the ISSM and represents largely urologists who participate in professional societies. Two-thirds of our respondents were fellowship-trained members potentially leading to a degree of sampling bias which should be taken into account while inferring these results. Thus, these data may not be generalizable to all physicians who treat hypogonadism. However, our data nevertheless identify a significant amount of variability in management of elevated estrogen levels in men on TTh for testosterone deficiency. Furthermore, the definition of elevated estrogen levels is variable based on laboratory and methodology. The biological implications of estrogen imbalance and its treatment remain incompletely understood, underscoring the need for additional work to better define the impact of elevated estrogen levels and their treatment in the setting of TTh for hypogonadism in order to develop standardized approaches to patient management.(30)

Conclusions

The present study reveals that approximately half of practitioners who treat hypogonadal patients check and monitor estrogen levels while patients are on therapy. The majority of practitioners initiate anti-estrogen therapy based on the presence of symptoms of hyperesterogenemia, and significant variability exists in dosing regimens for AIs, the drugs of choice for management of hyperestrogenemia. These data highlight the need for a more complete understanding of optimal monitoring for hyperestrogenemia and the appropriate time to initiate therapy. In addition, these data emphasize the need for optimized dosing regimens for the management of hyperestrogenemia in hypogonadal men on TTh. Better monitoring and standardization of therapy might eventually lead to availability of more objective research data and improved clinical outcomes.