Recovery of sperm production following testosterone replacement or anabolic steroids

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Nelson Vergel

The use of testosterone replacement therapy (TRT) for hypogonadism continues to rise, particularly in younger men who may wish to remain fertile. Concurrently, awareness of a more pervasive use of anabolic-androgenic steroids (AAS) within the general population has been appreciated. Both TRT and AAS can suppress the hypothalamic-pituitary-gonadal (HPG) axis resulting in diminution of spermatogenesis. Therefore, it is important that clinicians recognize previous TRT or AAS use in patients presenting for infertility treatment. Cessation of TRT or AAS use may result in spontaneous recovery of normal spermatogenesis in a reasonable number of patients if allowed sufficient time for recovery. However, some patients may not recover normal spermatogenesis or tolerate waiting for spontaneous recovery. In such cases, clinicians must be aware of the pathophysiologic derangements of the HPG axis related to TRT or AAS use and the pharmacologic agents available to reverse them. The available agents include injectable gonadotropins, selective estrogen receptor modulators, and aromatase inhibitors, but their off-label use is poorly described in the literature, potentially creating a knowledge gap for the clinician. Reviewing their use clinically for the treatment of hypogonadotropic hypogonadism and other HPG axis abnormalities can familiarize the clinician with the manner in which they can be used to recover spermatogenesis after TRT or AAS use.

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Defy Medical TRT clinic doctor

Nelson Vergel

History of Anabolic Androgenic Abuse Is Associated with Persistent Testicular Atrophy

Program: Abstracts - Orals, Poster Previews, and Posters
Session: SUN 176-202-Male Reproductive Endocrinology and Male Reproductive Tract (posters)
Bench to Bedside

Sunday, April 3, 2016: 1:15 PM-3:15 PM
Exhibit/Poster Hall (BCEC)

Poster Board SUN 193
Jon Bjarke Jarløv Rasmussen

Introduction: Abuse of anabolic androgenic steroids (AAS) causes a dramatic increase in plasma androgens and leads to testicular atrophy. The alterations are followed by hypogonadotropic hypogonadism due to a negative feedback mechanism of the hypothalamic-pituitary-testicular axis when abstinent from these substances. Whether AAS-induced hypogonadism and testicular atrophy are persistent is still unknown.

Aim: To study the reversibility of AAS-induced testicular atrophy and AAS- induced hypogonadism.

Methods and Results: Cross-sectional study among younger men (≤ 50 years): ongoing AAS abusers, n = 37; (age 31.4 ± 8.6 years, mean (SD)), former abusers, n = 25 (age 35.6 ± 6.9 years); median (IQR) abstinence duration from AAS of 2.1 (1.1 – 3.9) years and an age-matched control group who had never used AAS, n = 26 (age 31.4 ± 6.8 years). Ongoing and former AAS abusers did not differ in terms of median (IQR) duration of AAS abuse, 140 (78 – 234) weeks during 5.0 (2.0 – 10.0) years vs.130(50 – 260) weeks during 8.2 (4.0 – 11.5) years, P=0.47.Blood samples were obtained between 08:00 to 09:00 AM. Plasma Total-Testosterone (p-TT), normal reference range: 10.3 – 27.4 nmol/L, were measured by mass spectrometry and plasma gonadotropins were measured by immunoassay. Testicular size was assessed using Prader’s orchidometer by one investigator (JR). The testicular size was markedly reduced among AAS abusers and former AAS abusers as compared with the control group 12 (10 – 12) mL vs. 15 (12 – 20) mL vs. 25 (20 – 25) mL, P<0.01. Further, testicular size was negatively correlated (Spearman’s rank correlation coefficient) with duration of AAS abuse among ongoing AAS abusers (r= -0.34, P=0.04), and former AAS abusers (r= -0.41, P=0.03). Ongoing AAS abusers had markedly supraphysiological levels of p-TT: geometric mean (95%CI) 75.6 (54.2 – 105.4) nmol/L, maximum value 592.1 nmol/L. Hypogonadism was not present among former AAS abusers as p-TT did not differ between controls and former AAS abusers: 18.4 (16.3 – 20.8)nmol/L vs. 14.8 (12.7 – 17.2) nmol/L, age-adjusted difference:P=0.43. Further, measurement of plasma free-Testosterone did not change this finding. Ongoing AAS abusers had clearly suppressed plasma gonadotropin levels, p-FSH: 0.3 (0.1 – 0-4) IU/L and p-LH: <0.3 IU/L, while median(IQR) plasma gonadotropin levels did not differ between controls and former AAS abusers, p-FSH: 4.2 (3.6 – 5.9) IU/Lvs. 4.1 (3.4 – 6.3) IU/L,P=0.87and p-LH: 3.2 (2.5 – 3.9) IU/L vs.3.5 (2.2 – 4.1),P=0.76.

Conclusions: AAS-induced testicular atrophy may not be reversible even years after discontinuation of AAS abuse although we did not observe persistent hypogonadism in our cohort of former abusers of AAS. Testicular size is strongly associated with spermatogenesis and male fertility. Hence, it needs to be investigated further if former AAS abusers are in severe risk of irreversible impaired spermatogenesis and decreased fertility.

Nothing to Disclose: JBJR, CS, MS, FG, JF, CK
*Please take note of The Endocrine Society's News Embargo Policy atPR Resources for ENDO | Endocrine Society
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Pretty much everyone notices a reduction in volume. HCG helps somewhat in this area for most guys, but don't be surprised if you are still lower volume than pre TRT.


"Commonly used protocols"

10,000 IU hGC MWF in combination with FSH. I wonder if that's enough?

5,000 IU hGC MWF in combination with FSH , Farhat: 87 pt, 49 months, 56% pregnancy success. The conservative approach.

All in one cheek? I looked for the intra-testicullar Novocain injection protocol to prevent "desense" and coudln't find it.

Nelson Vergel

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Algorithm for the treatment of steroid induced infertility. TTh: testosterone therapy, AAS: androgenic-anabolic steroids, SA: semen analysis, T: testosterone, LH: luteinizing hormone, FSH: follicle stimulating hormone, HCG: human chorionic gonadotropin, SQ: subcutaneous, QOD: quaqua altera die (every other day), QD: quaque die (once a daily), Q7 days: quaque 7 days, rhFSH: recombinant human follicle stimulating hormone, TESE: testicular sperm extraction, m-TESE: microdissection testicular sperm extraction.

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Preserving testicular function and reproductive ability remains an ongoing challenge to practitioners prescribing TTh. Exogenous testosterone is known to decrease intratesticular testosterone and thus impair spermatogenesis. Indeed, in 1996 the World Health Organization investigated weekly injections of 200 mg testosterone enanthate (TE) as a form of contraception. The task force demonstrated that TE caused azoospermia in approximately 75% of men after only 6 months of use [71]. Both the American Urological Association and the Endocrine Society published guidelines in 2018 which recommend against TTh in men wishing to preserve fertility [2, 72]. Current evidence suggests, however, that adjuvant medications can be prescribed in an effort to maintain testicular health and fertility while receiving TTh.

Coadministration of HCG with TTh has been shown to help preserve spermatogenesis in men by maintaining physiologic intratesticular testosterone levels throughout treatment. In 2005, Coviello et al [58] demonstrated that TTh caused intratesticular testosterone levels to drop by 94% in otherwise healthy, reproductive-aged men. However, adding subcutaneous 250 IU HCG every other day to their TTh regimen prevented this precipitous fall with intratesticular testosterone levels only dropping 7% from baseline. Furthermore, men who received TTh and 500 IU of HCG every other day actually experienced an increase in their intratesticular testosterone by 26% [58]. This study showed that intratesticular testosterone could be reliably maintained while on TTh. Future studies would prove that spermatogenesis itself, and thus the male's fertility, could likewise be persevered throughout therapy.

A retrospective study published by Hsieh et al [73] in 2013 found that out of 26 men treated with TRT and intramuscular 500 IU HCG every other day, no patient became azoospermic. Nineteen of the 26 patients received injectable testosterone while seven were treated with transdermal testosterone gels. Mean serum hormone levels before vs during treatment were: testosterone 207.2 vs. 1,055.5 ng/dL (p<0.0001), free testosterone 8.1 vs. 20.4 pg/mL (p=0.02). No differences in SA parameters were observed during greater than 1 year of follow-up. During the study's follow-up, nine men established a pregnancy with his partner [73]. This study continues to serve as the foundation of ‘fertility-preserving’ TTh regimens currently utilized today.

Sensibly, all men wishing to preserve fertility while on TTh should obtain a baseline SA. During the initial consultation, it is also important to identify the patient's goals with regard to the timing of pregnancy (Table 1). If the patient desires pregnancy within the next 6 months and has not yet started, they should abstain from initiating TTh until pregnancy has been achieved. If they desire pregnancy within 6 months and are already receiving TTh, it is recommended that they stop all TTh and follow a recovery regimen identical to what was detailed in the previous section.

Source: Management of Anabolic Steroid-Induced Infertility: Novel Strategies for Fertility Maintenance and Recovery

Nelson Vergel

Normalizing Testosterone and Semen Production After Stopping TRT or Anabolic Steroids

Testosterone replacement therapy (TRT) or anabolic steroid (AAS) use impairs sperm production (spermatogenesis) by promoting negative feedback on both the hypothalamus and pituitary gland. This reduces the pulsatile secretion of gonadotropin-releasing hormone GnRH and luteinizing hormone LH respectively. The loss of LH secretion shuts down the production of testosterone by testicular Leydig cells which in turn significantly reduces intratesticular (inside the testicles) testosterone levels. This altering of the hypothalamus-pituitary-gonadal (HPG) axis and drop of intratesticular testosterone can lead to a lack of sperm within ten weeks of starting TRT. Even more alarming is the fact that up to 10% of men can remain azoospermic after the cessation of TRT.

Human Chorionic Gonadotropin (hCG) therapy can help preserve spermatogenesis in men undergoing TRT by maintaining intratesticular testosterone levels. Some studies have been shown that stimulating follicle hormone (FSH) alone cannot initiate or maintain spermatogenesis in hypogonadal men leading to the discovery of the importance of intratesticular testosterone in spermatogenesis. In healthy eugonadal (normal testosterone) men selected to undergo TRT, it was shown that their intratesticular testosterone levels dropped by 94%. However, in those who received hCG 250 IU SC every other day along with TRT, their intratesticular testosterone levels only dropped 7%. Additionally, in men who received TRT and 500 IU of hCG every other day an increase in intratesticular testosterone by 26% from baseline was observed. This proved that co-administering low dose hCG could maintain intratesticular testosterone in those undergoing TRT. It was later shown that not only is intratesticular testosterone increased with co-administration hCG but spermatogenesis is preserved as well at one year follow up. These studies proved that by concomitant hCG administration with TRT spermatogenesis, and thus potentially fertility could be preserved.

All men wishing to preserve fertility while on TRT should have a baseline semen analysis (SA). Next, it is important to determine the appropriate dosing regimen of hCG based on the timeline for the desired pregnancy. For men who wish to obtain pregnancy within six months, it has been suggested to discontinue TRT and start 3,000 IU of hCG intramuscular, or subcutaneous every other day. SA should then be performed every two months. Clomiphene citrate 12.5-25 mg daily can be added or omitted to promote FSH production. Dr. Ramasamy and his team in Miami suggest including of clomiphene citrate in all men who already have low sperm count on TRT alone. Clomiphene can be omitted in men who are initiating TRT and hCG simultaneously and have normal semen parameters.

If semen parameters fail to improve and FSH remains low, compounded FSH 75 IU (Empower Pharmacy) every other day can be added. In men who desire pregnancy within 6–12 months TRT can be continued with co-administration of 500 IU of HCG every other day ± clomiphene citrate can be used. For men who do not desire to preserve fertility testicular size can be maintained while undergoing TRT with 1,000 to 1,500 IU of HCG given weekly which is enough to maintain pre-TRT levels of intratesticular testosterone in two-thirds of men.



  • Transl Androl Urol. 2018 Jul; 7(Suppl 3): S348–S352.
  • J Urol. 2013 Feb; 189(2):647-50.
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Nelson Vergel

Eur J Endocrinol. 2022 Jan 1;EJE-21-0608.R2. doi: 10.1530/EJE-21-0608. Online ahead of print.

Recovery of Male Reproductive Function After Ceasing Prolonged Testosterone Undecanoate Injections

David J Handelsman 1, Reena Desai 2, Ann J Conway 3, Nandini Shankara-Narayana 4, Bronwyn Ga Stuckey 5, Warrick J Inder 6, Mathis Grossmann 7, Bu Beng Yeap 8, David Jesudason 9, Lam P Ly 10, Karen Bracken 11, Gary Allen Wittert 12

Context: The time course of male reproductive hormone recovery after stopping injectable testosterone undecanoate (TU) treatment is not known.

Objective: To investigate rate, extent, and determinants of reproductive hormone recovery over 12 months after stopping TU injections.

Methods: Men (n=303) with glucose intolerance but without pathologic hypogonadism who completed a 2-year placebo(P)-controlled randomized clinical trial of TU treatment were recruited for a further 12 months while remaining blinded to treatment. Sex steroids (T, DHT, E2, E1) by LCMS, LH, FSH and SHBG by immunoassays and sexual function questionnaires (Psychosexual Diary Questionnaire (PDQ), International Index of Erectile Function (IIEF), SF-12) were measured at entry (three months after last injection) and 6, 12, 18, 24, 40 and 52 weeks later.

Results: In the nested cohort of TU-treated men, serum T was initially higher but declined to 12 weeks remaining stable thereafter with serum T and SHBG 11% and 13%, respectively, lower than P-treated men. Similarly, both questionnaires showed initial carryover higher scores in T-treated men, but after weeks 18 showed no difference between T and P treated men. Initially fully suppressed serum LH and FSH recovered slowly towards the participant's own pre-treatment baseline over 12 months since last injection.

Conclusions: After stopping 2 years of 1000 mg injectable TU treatment, full reproductive hormone recovery is slow and progressive over 15 months since last testosterone injection but may take longer than 12 months to be complete. Persistent proportionate reduction in serum SHBG and T reflects lasting exogenous T effects on hepatic SHBG secretion rather than androgen deficiency.
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