Awareness: An effective tool to treat and prevent an increasingly common cause of male factor infertility

Consider This

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Authors:

Alexander Michael Quaas, M.D., Ph.D. (a, b, c), Evan Reshef, M.D. (d)

(a) Clinic for Reproductive Medicine and Gynecologic Endocrinology
University Hospital, University of Basel
Basel, Switzerland

(b) Reproductive Partners San Diego
San Diego, California

(c)Division of Reproductive Endocrinology and Infertility
University of California
San Diego, California

(d) Department of Obstetrics and Gynecology
University of Arizona College of Medicine
Phoenix, Arizona

Consider This:

“Are you tired all the time? Do you feel depressed, with lack of energy? And do you feel like you are no longer the animal in bed that you used to be? Then you should make an appointment at our men’s clinic- treatment guaranteed!”

Radio commercials such as this one, advertising an increasing number of “low T clinics” can be heard throughout the United States. There has been a sharp increase in Testosterone (T) prescription over the last decade  [1, 2] , along with an increased awareness of androgen deficiency syndromes and the introduction of a greater spectrum of commercial androgen replacement products [3].

In the physiologic state, intratesticular T concentrations are much higher than plasma T concentrations and essential for spermatogenesis to occur. With the use of anabolic-androgenic steroids (AAS) such as exogenous T supplementation, feedback suppression of the hypothalamic-pituitary-gonadal (HPG) axis leads to hypogonadotropic hypogonadism via inhibition of pulsatile hypothalamic GnRH release [1]. Decreased intratesticular testosterone concentrations suppress sperm production. While natural testosterone concentrations [4, 5] and sexual function [6] decrease with increasing male age, exogenous androgen supplementation has only been approved and recommended for the treatment of clinically significant hypogonadism [7]. According to the Endocrine Society, supplementation should only be considered in men with a decreased serum testosterone level measured on 3 separate occasions between 8-10am, in combination with signs and symptoms suggestive of hypogonadism. Specific signs and symptoms include decreased libido, decreased morning erections, loss of body hair, decreased bone mineral density, gynecomastia and small testes.

Less specific symptoms include fatigue, depression, anemia, decreased muscle strength and increases in fat mass [7]. The Endocrine Society recommends against screening for androgen deficiency in the general population, as there are no clinical trials assessing the effectiveness of screening strategies. According to the Food and Drug Administration (FDA), T supplementation is not approved for improvement of strength, athletic performance, appearance or normal age related problems (https://www.fda.gov). Recently, there has been a sharp increase in T use in healthy middle-aged and older men due to direct-to-consumer advertising encouraging use for non-specific symptoms, such as decreases in energy and sexual interest [2, 3].

 Frequently, treatment is prescribed in the absence of sustained subnormal serum T concentrations, or on a “trial basis”. Male factor infertility is estimated to be the sole factor in 20-30% and a contributing factor in up to 50% of couples presenting for infertility evaluation [8]. The proportion of male factor infertility secondary to exogenous androgen supplementation is currently unknown.

 

Study objective

The primary aim of our study was to assess the awareness of the fertility effects of T supplementation amongst AAS users in retrospective cohort of consecutive patients presenting to an academic infertility clinic. As secondary aims, we sought to examine the prevalence of T use in a cohort of patients presenting for their first infertility evaluation, as well as patterns of T use (including prescribing source and preparation) and effects on semen analysis parameters. 

 

Materials and Methods

We conducted a retrospective cohort study in 303 consecutive couples presenting for initial infertility evaluation at a university-based infertility clinic from January 1, 2013 to October 1, 2015 [9].

At the initial visit, each couple was routinely asked about AAS use in the male partner. If AAS use was identified, one investigator (ER) conducted a phone interview with the male partner using the following questionnaire:

  • When did you start androgen treatment?
  • What was the indication?
  • What was the dose and the route of administration?
  • Did you receive a prescription for the androgen preparation?
  • If yes, where did you obtain the prescription?
  • Were potential fertility effects of androgen supplementation discussed with you at the time of the prescription?
  • If you did not have a prescription, how did you obtain the androgen supplementation?

 Results were analyzed using basic descriptive statistical methods.

 

Results

Among 303 consecutive couples presenting for initial infertility evaluation, exogenous T use was identified in 17 male partners, for a prevalence of 5.6%.

Of the 17 identified male partners, 13 (76.5%) agreed to participate in the phone survey. 7/13 (53.8%) used physician-prescribed T. 4/13 (23.1%) used over-the-counter supplements containing T. 2/13 (15.4%) denied T use, despite having reported it at the time of initial consultation. Of the 7 patients using prescription T supplementation, all 7 (100%) used T injections, with 2/7 (28.6%) reporting additional use of a gel, and 1/7 (14.3%) reporting additional use of a patch. The indication for T supplementation was ‘‘low T’’ in all cases. T therapy was prescribed by family physicians (4/7) or urologists (3/7).

3 of 7 patients (42.9%) reported awareness of detrimental effects of T use on fertility at the time of treatment initiation, but only 2 of 7 (28.6%) reported that these had been mentioned by the prescribing physician at the time of the initial prescription.

The semen analysis was abnormal in all 7 patients on physician-prescribed T supplementation, with a finding of azoospermia in 3 of 7 patients (Table 1).

Discussion

Our pilot study demonstrates that T supplementation was prevalent in the convenience sample of couples presenting for initial infertility evaluation (5.6%), either physician-prescribed or privately obtained.

Only a minority of patients receiving physician-prescribed T supplementation were counseled regarding fertility effects at the time of treatment initiation.

Although it is possible to “rescue” male fertility by discontinuing T supplementation, and with the use of injectable gonadotropins [10], the recovery of spermatogenesis depends on individual factors such as age of the patient and duration of supplementation [1], and unpleasant T withdrawal symptoms may occur after cessation of treatment. 

A majority of patients on physician-prescribed T supplementation surveyed in our study lacked awareness regarding its fertility effects. Compounding the problem is the fact that even provider awareness of this issue is low.

A 2012 survey of 7,745 practicing American Urological Association members demonstrated that 25% of respondents would treat infertile males with testosterone while the patient actively pursued pregnancy [11]. It can be assumed that there is even less awareness of the fertility effects of exogenous AAS amongst members of other specialties, such as family physicians, and in the general population. When men obtain AAS in non-medical settings, such as over the internet [12], no opportunity for counseling by a medical provider exists.  

The current sharp increase in exogenous T use in healthy men due to direct-to-consumer advertising [2, 3], along with a lack of counseling, will inevitably lead to an increasing incidence of male factor infertility secondary to AAS-induced hypogonadism. Asking about androgen use should be part of the routine initial infertility evaluation; and male and female infertility providers need to raise awareness of this emerging public health problem amongst their patients and colleagues, and be a voice of caution against the radio commercials by “low T” clinics.

REFERENCES:

1.         Rahnema, C.D., et al., Anabolic steroid-induced hypogonadism: diagnosis and treatment. Fertil Steril, 2014. 101(5): p. 1271-9.

2.         Moss, J.L., L.E. Crosnoe, and E.D. Kim, Effect of rejuvenation hormones on spermatogenesis. Fertil Steril, 2013. 99(7): p. 1814-20.

3.         Nigro, N. and M. Christ-Crain, Testosterone treatment in the aging male: myth or reality? Swiss Med Wkly, 2012. 142: p. w13539.

4.         Morley, J.E., et al., Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism, 1997. 46(4): p. 410-3.

5.         Practice Committee of American Society for Reproductive Medicine in collaboration with Society for Male, R. and Urology, Androgen deficiency in the aging male. Fertil Steril, 2008. 90(5 Suppl): p. S83-7.

6.         Eisenberg, M.L. and D. Meldrum, Effects of age on fertility and sexual function. Fertil Steril, 2017. 107(2): p. 301-304.

7.         Bhasin, S., et al., Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 2010. 95(6): p. 2536-59.

8.         Agarwal, A., et al., A unique view on male infertility around the globe. Reprod Biol Endocrinol, 2015. 13: p. 37.

9.         Reshef, B.A., et al., Testosterone (T) use in male partners of couples presenting for the initial infertility evaluation: prevalence, usage patterns and fertility awareness. Fertil Steril, 2016. 105(2): p. e35.

10.       Menon, D.K., Successful treatment of anabolic steroid-induced azoospermia with human chorionic gonadotropin and human menopausal gonadotropin. Fertil Steril, 2003. 79 Suppl 3: p. 1659-61.

11.       Ko, E.Y., et al., Empirical medical therapy for idiopathic male infertility: a survey of the American Urological Association. J Urol, 2012. 187(3): p. 973-8.

12.       Pirola, I., et al., Anabolic steroids purchased on the Internet as a cause of prolonged hypogonadotropic hypogonadism. Fertil Steril, 2010. 94(6): p. 2331 e1-3.

 

 


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Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders. The journal publishes juried original scientific articles in clinical and laboratory research relevant to reproductive endocrinology, urology, andrology, physiology, immunology, genetics, contraception, and menopause. Fertility and Sterility® encourages and supports meaningful basic and clinical research, and facilitates and promotes excellence in professional education, in the field of reproductive medicine.

2 Comments

Go to the profile of Micah J Hill
Micah J Hill 3 months ago

Alex, thanks for sharing your paper and data.  6% is a concerning number of men on testosterone.  I've never queried our military infertility patients, but we anecdotally see it frequently as well.

Go to the profile of Alexander Quaas
Alexander Quaas 3 months ago

Thank you for your comment Micah. It really is an increasingly common cause of (male) infertility. In addition to the effect on semen parameters, I often noticed that this issue was a strain on relationships in several different ways: 

1) because the male partner may not be transparent about the extent or duration of T use (or even about the fact that he is using supplementation at all), and 

2) because T withdrawal upon cessation of supplementation for fertility reasons may lead to unpleasant mood swings and depression.

Our hope is that our "Consider This" piece will motivate fertility providers to routinely ask about T use and raise awareness about the fact that T supplementation is essentially a form of male contraception.