For decades, clomiphene citrate (CC) has served as the cornerstone of ovulation induction in women with anovulatory infertility, particularly in polycystic ovary syndrome (PCOS). Its anti-estrogenic action on hypothalamic estrogen receptors stimulates gonadotropin release and follicular development. Yet this same mechanism paradoxically leads to endometrial thinning and suboptimal uterine receptivity, one of the principal reasons that ovulation does not always translate into pregnancy.
In recent years, research has shifted toward agents that could counteract the anti-estrogenic endometrial effects of CC without diminishing its ovulatory efficacy. Among these, tadalafil, a phosphodiesterase type-5 (PDE5) inhibitor better known for its vascular and smooth muscle effects, has drawn clinical attention. The drug’s ability to enhance nitric oxide (NO)-mediated vasodilation and uterine blood flow makes it a promising adjunct to standard ovulation protocols.
A prospective study published in The Middle East Fertility Society Journal investigated precisely this question: Can tadalafil improve endometrial thickness and pregnancy rates when combined with clomiphene citrate? The results are not only encouraging—they illuminate a physiological connection between endothelial pharmacology and endometrial receptivity.
Study Design: A Targeted Clinical Inquiry
The investigators conducted a prospective, randomized, controlled clinical study involving 150 infertile women aged 20–35 years with regular menstrual cycles and patent fallopian tubes, all diagnosed with anovulation or oligo-ovulation. None had underlying systemic disease, pelvic pathology, or hormonal abnormalities.
Participants were randomly divided into three equal groups of 50 women each:
- Group A (Clomiphene Citrate + Tadalafil): Received clomiphene citrate 100 mg/day (cycle days 2–6) plus tadalafil 5 mg/day (cycle days 7–14).
- Group B (Clomiphene Citrate only): Received clomiphene citrate 100 mg/day alone.
- Group C (Human Menopausal Gonadotropin, hMG): Received intramuscular hMG 75 IU daily starting on cycle day 7 until adequate follicular response was observed.
The primary endpoints were endometrial thickness (ET) and pattern on the day of ovulation trigger, while secondary outcomes included ovulation rate and pregnancy rate per cycle.
Follicular monitoring was conducted by transvaginal ultrasonography beginning on cycle day 10, with human chorionic gonadotropin (hCG) 10,000 IU administered once a leading follicle reached ≥18 mm. Luteal support was provided with vaginal progesterone 400 mg daily for 10 days post-ovulation.
Baseline Parity: Groups Well Matched for Comparison
The three groups were demographically and clinically comparable at baseline:
- Mean age: 27.8 ± 3.4 years (range 20–35).
- Mean BMI: 26.2 ± 2.7 kg/m².
- Duration of infertility: 3.2 ± 1.5 years.
There were no statistically significant differences among groups in menstrual regularity, ovarian volume, or baseline serum FSH, LH, or estradiol. This ensured that subsequent intergroup differences could be attributed to the pharmacologic interventions rather than intrinsic variation in ovarian reserve or endocrine function.
Endometrial Thickness: Tadalafil Shows a Clear Edge
Quantitative Findings
By the day of ovulation trigger, endometrial thickness (ET) was markedly different among the three groups:
- Group A (CC + Tadalafil): 9.3 ± 1.2 mm
- Group B (CC only): 7.4 ± 1.1 mm
- Group C (hMG): 9.8 ± 1.3 mm
The difference between the tadalafil and clomiphene-only groups was highly significant (p < 0.001), while ET in the tadalafil group closely approximated that achieved with hMG, a considerably more expensive and invasive regimen.
This improvement indicates that tadalafil effectively reverses CC-induced endometrial thinning, most likely through enhanced uterine perfusion and oxygenation.
Endometrial Pattern
Endometrial echogenicity, another marker of receptivity, improved in the tadalafil group. A trilaminar (type C) pattern was observed in 80% of tadalafil cycles versus only 46% of CC-only cycles (p < 0.01). In the hMG group, 86% achieved trilaminar morphology.
These morphological improvements parallel the increased ET measurements, suggesting a global improvement in endometrial readiness rather than a mere numerical thickening.
Ovulation and Follicular Response
Clomiphene citrate predictably induced multiple follicular development. The mean number of mature follicles (≥18 mm) was similar across groups:
- Group A (CC + Tadalafil): 1.8 ± 0.4
- Group B (CC only): 1.9 ± 0.6
- Group C (hMG): 2.0 ± 0.5
No significant differences were observed (p > 0.05), indicating that tadalafil did not alter folliculogenesis—its benefit lies specifically in enhancing uterine vascular response, not ovarian stimulation.
The ovulation rate, confirmed by mid-luteal progesterone >10 ng/mL and sonographic collapse of the leading follicle, was likewise comparable among the three groups (88%, 84%, and 92%, respectively). Thus, tadalafil does not affect the ovulatory mechanism itself, maintaining clomiphene’s efficacy while addressing its endometrial shortcomings.
Pregnancy Outcomes: Translating Physiology into Success
Ultimately, the clinical question is not whether the endometrium looks thicker, but whether this translates into conception. Here again, tadalafil made a measurable difference.
- Pregnancy rate per cycle:
- Group A (CC + Tadalafil): 26%
- Group B (CC only): 12%
- Group C (hMG): 28%
The improvement between Group A and Group B was statistically significant (p < 0.05). Importantly, pregnancy rates in the tadalafil group nearly matched those of the hMG regimen, suggesting that tadalafil provides a non-invasive, cost-effective alternative to injectable gonadotropins in selected patients.
No cases of ovarian hyperstimulation syndrome (OHSS) or multiple pregnancy were reported. The absence of systemic adverse effects underscores the safety and tolerability of low-dose tadalafil in this context.
Mechanistic Insights: Linking Endothelial Pharmacology to Endometrial Receptivity
To appreciate the elegance of these findings, one must revisit the physiology of endometrial development.
Endometrial proliferation and vascular remodeling are governed by estrogen-driven angiogenesis and nitric oxide-dependent vasodilation. Clomiphene citrate, by antagonizing estrogen receptors in the endometrium, suppresses local NO synthesis, resulting in vasoconstriction and reduced perfusion. The downstream effect is a hypoxic, thin, and poorly receptive endometrial layer, even amid adequate follicular maturation.
Here, tadalafil intervenes. As a selective PDE5 inhibitor, it prevents the degradation of cyclic guanosine monophosphate (cGMP), the intracellular messenger of NO signaling. Elevated cGMP induces smooth muscle relaxation in uterine arterioles, thereby increasing blood flow and oxygen delivery to the endometrial stroma.
Additionally, PDE5 inhibition enhances the expression of vascular endothelial growth factor (VEGF) and prostaglandin E₂, both essential mediators of angiogenesis and glandular proliferation. These mechanisms collectively transform the endometrium from a hypoxic to a receptive state.
In short, tadalafil rebalances the vascular environment that clomiphene disturbs—a pharmacologic counterpoint that turns a paradox into synergy.
Comparative Pharmacologic Context
The success of tadalafil in this study aligns with earlier research on other vasodilators such as sildenafil citrate administered vaginally. However, tadalafil offers several advantages:
- Longer half-life (≈17 hours) ensures sustained vascular enhancement.
- Oral route improves compliance compared to vaginal formulations.
- Selective PDE5 inhibition reduces off-target systemic effects.
By contrast, hMG, though highly effective, involves repeated injections, rigorous monitoring, and higher risk of hyperstimulation. Tadalafil therefore occupies a unique therapeutic middle ground: oral convenience with gonadotropin-like endometrial benefits.
Safety Profile and Adverse Events
In this study, no significant adverse effects were reported among tadalafil recipients. Minor, transient complaints such as headache and flushing occurred in only 4% of cases, none leading to discontinuation. Blood pressure, heart rate, and liver function tests remained stable.
These findings echo tadalafil’s established cardiovascular safety record in other populations. When used at 5 mg/day, systemic hemodynamic changes are minimal, rendering it compatible even with mild hypertension or controlled cardiovascular conditions—though prudence dictates individualized assessment before use in reproductive protocols.
Clinical Implications: Redefining Ovulation Induction Protocols
The implications of these findings extend beyond statistical significance. They redefine the pharmacologic logic of ovulation induction.
Clomiphene citrate remains first-line therapy for anovulatory infertility due to its affordability, oral administration, and predictable ovulatory response. Yet its anti-estrogenic endometrial effect continues to frustrate clinicians. Adjunct tadalafil offers a physiological remedy without introducing gonadotropin complexity or cost.
Clinically, this approach could be particularly advantageous for:
- Patients with thin endometrium (<8 mm) in prior CC cycles.
- Resource-limited settings where gonadotropins are unaffordable or unavailable.
- Women reluctant to undergo injections or intensive monitoring.
Moreover, the regimen’s simplicity—adding tadalafil for seven days during the late follicular phase—enhances compliance and patient satisfaction.
In the broader reproductive endocrinology landscape, this strategy demonstrates how targeted vascular pharmacology can correct iatrogenic microenvironmental deficiencies rather than replacing entire hormonal pathways.
Interpretation and Broader Significance
Beyond endometrial thickening, tadalafil’s impact invites speculation about its influence on implantation and placental development. Improved uterine perfusion may favor early trophoblastic invasion, potentially reducing miscarriage risk in future studies.
Furthermore, tadalafil’s anti-oxidative and endothelial protective properties, well established in cardiovascular research, could mitigate subtle inflammatory processes implicated in unexplained infertility.
These hypotheses await validation through larger, multi-cycle trials, but the principle is clear: reproductive success is as dependent on microvascular health as it is on endocrine stimulation.
Limitations of the Study
While the study provides compelling clinical evidence, certain limitations must temper its interpretation:
- Sample Size and Single-Center Design – Larger, multicenter trials would bolster generalizability.
- Short-Term Follow-Up – Outcomes were assessed per cycle; cumulative pregnancy or live-birth rates were not evaluated.
- Lack of Doppler Flow Indices – Direct measurement of uterine artery perfusion could have strengthened the mechanistic argument.
- Absence of Blinding – The open-label design introduces a minor potential for observer bias, though objective endpoints (ET, ovulation) mitigate this concern.
Despite these, the study represents one of the earliest controlled clinical validations of tadalafil’s reproductive potential.
Conclusion: A New Frontier in Endometrial Pharmacotherapy
The combination of clomiphene citrate and tadalafil yields a statistically and clinically significant improvement in endometrial thickness, echogenic pattern, and pregnancy rate compared with clomiphene alone. The addition of tadalafil not only offsets CC’s anti-estrogenic vascular effects but does so safely and economically, rivaling the efficacy of injectable gonadotropins.
This synergy underscores a paradigm shift in reproductive medicine—from manipulating hormones to optimizing tissue perfusion. As our understanding of endometrial biology deepens, agents like tadalafil may become integral to individualized ovulation induction regimens, helping bridge the gap between ovulation and implantation.
Future trials should examine cumulative conception rates, Doppler indices, and endometrial molecular markers to confirm whether tadalafil’s effects extend beyond morphology into true endometrial receptivity at the genomic level. Until then, the evidence stands strong: improving blood flow can indeed improve fertility.
FAQ
1. Can tadalafil replace gonadotropin therapy in ovulation induction?
Not entirely. While tadalafil improves endometrial parameters comparably to hMG in this study, it does not stimulate folliculogenesis. It should be viewed as an adjunct to clomiphene, not a substitute for gonadotropins when advanced stimulation is required.
2. Is tadalafil safe for reproductive-age women?
At low daily doses (5 mg), tadalafil demonstrated an excellent safety profile with minimal side effects. Nevertheless, it should be prescribed under specialist supervision, considering cardiovascular history and drug interactions.
3. How long should tadalafil be used during the cycle?
In this protocol, tadalafil was administered from cycle days 7–14, corresponding to the late follicular phase when endometrial growth and vascularization peak. Extending use beyond ovulation offers no additional benefit and is not recommended.
Reference:
El Sayed M. et al. Effect of Oral Tadalafil on Endometrial Thickness in Patients Receiving Clomiphene Citrate for Ovulation Induction. Middle East Fertility Society Journal. 2018; 23(2):135-141.
