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Study analysis · Asian Journal of Andrology · 2019

The breast-cancer drug that made sperm counts more than double—without a single pregnancy outcome reported.

In 8 small studies of 517 infertile men, aromatase inhibitors improved hormone and sperm lab numbers, but we still don't know if they help couples have a baby.

Reading level
Low certainty
Level 2a · Systematic review of cohort studiesAssociation, not causationNo causal claims

Overview

What the study found

The study in plain English — the bottom line, every takeaway we extracted, and what to do with them.

In simple terms

This study combined results from several smaller studies to see if certain medicines help men with fertility problems. It found that the medicines might improve hormone levels and sperm, but because the studies were not all high-quality experiments, we can't be sure the medicines actually cause the improvement. We need more careful experiments to know for sure.

What’s the bottom line?

Researchers pooled 8 studies of men with infertility and low testosterone and/or low testosterone-to-estradiol ratio. They looked at whether aromatase inhibitor drugs changed hormones and sperm.

How strong is this study?

The researchers did a good job searching for all relevant studies and analyzing them together, but the studies they found were of mixed quality—some were randomized experiments, but many were not, and they were small. That means we should be cautious about trusting the results completely.

Reporting

40 / 100

  • COI disclosure+40/40
  • Data availabilitydata not shared
  • Code availabilitycode not shared
Methodology

0 / 100

  • Randomizationnot randomized
  • Blindingnot blinded
  • Control groupno control group
  • Sample sizeno sample size reported
  • Follow-upno follow-up reported
Publication

100 / 100

Statistical

77 / 100

  • P-values+15/15
  • Effect size+20/20
  • Confidence intervals+15/15
  • Pre-registrationnot pre-registered

Each component is scored out of 100 and then capped by the study design — a case series cannot reach the ceiling a randomised trial can, however well it is reported.

Where it sits

RCT reviews

Max 100

Randomized Trials

Max 90

Reviews of Cohort Studies

Max 85

Cohort Studies

Max 72

Reviews of Case-Control Studies

Max 63

Case-Control Studies

Max 58

Cross-Sectional & Case Series

Max 50

Expert Opinion

Max 5
StrongerWeaker
Reviews of Cohort Studies
Level 2a
47

47 / 100

Probability of being correct

Systematic reviews and meta-analyses of cohort studies. They sit above a single cohort study but below a single randomized trial, because the underlying evidence is still observational.

This design cannot establish causation — the findings describe an association, not a cause. The review includes a mix of randomized and non-randomized studies, with only two RCTs, and high heterogeneity (I2 > 95%). Many studies lacked placebo control, and there are no pregnancy outcomes. Thus, causation cannot be established.

COI Unknown

Could not determine conflict of interest status

Not Disclosed

No conflict of interest or funding statements were included in the provided text, so potential conflicts cannot be assessed.

Undisclosed — Suspicious

The provided text lacks a COI/funding section and author affiliations. No industry funding or author conflicts are evident, but absence of disclosure limits assessment. The review itself reports no primary data.

Key takeaways

  1. 01

    Across 517 men, testosterone rose by 155.5 ng/dL on average (a 48.5% relative increase).

  2. 02

    The testosterone-to-estradiol ratio rose by 16.7 points (a 227% relative increase).

  3. 03

    Sperm concentration rose by 9.2 million/mL (a 116.3% relative increase).

  4. 04

    Sperm motility rose by 8.7 percentage points (a 47% relative increase).

  5. 05

    About 14 of 436 men (3.2%) stopped the drug because of side effects.

  6. 06

    No pregnancy outcomes were reported.

  7. 07

    These are absolute changes in lab and semen measurements, not pregnancy or live-birth rates.

  8. 08

    On average, sperm concentration went from about 7.9 to 17.2 million/mL, and motility went from about 18.6% to 27.4%.

  9. 09

    The study did not report whether more couples actually got pregnant.

  10. 10

    The absolute side-effect discontinuation rate was 3.2%.

  11. 11

    Because heterogeneity was high, the results are uncertain.

Surprising findings

  • No pregnancy or live-birth outcomes were reported in any included study.For a treatment aimed at male infertility, the most patient-important outcome—pregnancy—was completely missing, leaving the clinical benefit unproven.
  • Azoospermic men showed no overall sperm recovery, yet one letrozole study found sperm in all 6 azoospermic patients.This contradicts the pooled finding and suggests either a drug-specific effect, a small-sample fluke, or a specific subgroup that responds.
  • Sperm concentration more than doubled on average, but average motility remained below the normal threshold.People often assume sperm improvements move together. Here, concentration crossed into normal range on average, but motility stayed at 27.4%, well below the usual 40% cutoff.
  • Heterogeneity was extremely high for several pooled outcomes, with I2 up to 97.85%.An I2 that high means the studies disagree so much that a single pooled number is hard to interpret—yet the meta-analysis still reports statistically significant benefits.

Practical takeaways

If you are a man with infertility and low testosterone or a low T/E2 ratio, ask your doctor about whether aromatase inhibitors are appropriate—but understand that pregnancy benefit is unproven.

This is off-label use based on 8 small, mostly nonrandomized studies with high heterogeneity and no pregnancy or live-birth outcomes.

low confidence

If you take an aromatase inhibitor for male infertility, monitor liver enzymes, libido, and bone health with your clinician.

Side effects led 3.2% of men to discontinue; subclinical hepatic dysfunction occurred in 5.5%, libido loss in 2.5%, and one study showed osteoporosis in 6.9% on letrozole vs 5.5% on placebo, with limited follow-up.

medium confidence

Do not self-prescribe aromatase inhibitors for testosterone boosting or bodybuilding based on this study.

The study population was infertile/hypogonadal men, not healthy men seeking performance enhancement, and long-term safety is unknown.

high confidence

For men with azoospermia, do not expect aromatase inhibitors alone to reliably bring sperm back; discuss sperm retrieval options with a fertility specialist.

Pooled data from 66 azoospermic men showed no overall sperm recovery, though one small letrozole study found sperm in all 6 patients.

medium confidence

Why this study matters

Testosterone jumped by 155 ng/dL—a 48.5% relative increase

Across 7 studies of 417 men, average serum testosterone rose from 320.1 ± 98.2 ng/dL to 475.6 ± 60.3 ng/dL, an absolute mean increase of 155.5 ng/dL (48.5% relative increase). The pooled standardized mean difference was 4.443 (95% CI 1.634–7.253; P=0.002), but heterogeneity was extremely high (I2=97.85%).

Low testosterone affects energy, mood, and fertility, and men increasingly seek off-label hormone treatments. This suggests blocking estrogen can raise testosterone substantially—at least on paper.

T/E2 ratio exploded by 227% relative—but absolute rise was 16.7 points

Across 8 treatment arms of 374 men, the testosterone-to-estradiol ratio rose from 7.4 ± 1.6 to 24.1 ± 10.1, an absolute mean increase of 16.7 (227% relative increase). The pooled SMD was 8.006 (95% CI 5.813–10.200; P<0.001), with high heterogeneity (I2=95.8%).

A low T/E2 ratio is often used to select men for aromatase inhibitors, so this is the core hormone target. The relative change is huge, but the absolute numbers started very low.

Sperm concentration more than doubled: +9.2 million/mL absolute, 116.3% relative

Across 4 treatment arms, average sperm concentration rose from 7.9 ± 5.4 ×10^6/mL to 17.2 ± 8.1 ×10^6/mL, an absolute increase of 9.2 ×10^6/mL (116.3% relative increase). The pooled SMD was 2.595 (95% CI 1.817–3.372; P<0.001), with moderate heterogeneity (I2=65.1%).

The average moved from clearly subfertile to just above the WHO normal threshold of 15 million/mL, which sounds dramatic—but it is still an average, not a guarantee for any individual.

Sperm motility improved by 8.7 percentage points absolute (47% relative), but stayed low

Across 5 studies, average sperm motility rose from 18.6% ± 12.4% to 27.4% ± 12.5%, an absolute increase of 8.7 percentage points (47% relative increase). The pooled SMD was 2.291 (95% CI 1.073–3.510; P<0.001), with high heterogeneity (I2=93.3%).

Motility is crucial for sperm reaching the egg, and 27.4% is still below the typical normal threshold of 40%. The numbers improved, but many men may remain in the abnormal range.

No pregnancy or live-birth outcomes were reported

The meta-analysis found no data on whether couples actually conceived or had a live birth. The authors state that because pregnancy and live-birth outcomes were not available, the effect of aromatase inhibitors on actual fertility remains unproven.

This is the elephant in the room: the whole point of male infertility treatment is helping couples have a baby, not just improving lab numbers.

Azoospermia: generally no sperm recovery, except one small letrozole study

In pooled data from 66 azoospermic men across 3 studies, no sperm were found in the ejaculate at follow-up. But one letrozole study reported sperm retrieval in all 6 azoospermic patients, and another found sperm in 4 of 17 (23.5%) azoospermic men, though that did not reach statistical significance (P=0.125).

This is a huge contrast: most azoospermic men did not recover sperm, but one small study suggests a possible signal. It could raise false hope or point to a real subgroup effect.

Side effects: 3.2% stopped therapy, but bone and liver signals matter

Among 436 men, 14 (3.2% absolute) discontinued due to side effects. Common issues were subclinical hepatic dysfunction (5.5%, 24/436), decreased or lost libido (2.5%, 11/436), and drug intolerance (2.3%, 10/436). In one study, osteoporosis occurred in 6.9% of letrozole-treated men versus 5.5% of placebo-treated men, but follow-up was limited.

Aromatase inhibitors are not benign—they can affect liver enzymes, sex drive, and potentially bone density. Men considering off-label use need monitoring.

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Standing

The people behind it

The researchers who wrote the study this analysis is built on.

Authored by

9 researchers

If this is your work, this is how we attribute it on Fit Body Science. Gian Maria Busetto is listed as the lead author.