Live High, Train Low (LHTL) Four-Week Physiological Adaptation Fully Explained: How Normobaric Hypoxia at 2,000–2,500m Drives EPO Pulses and Red Blood Cell Volume Expansion

1. Introduction and Frontier Research Background

1.1 The Training Paradigm Shift from “Live High-Train High” to “Live High-Train Low”

Since the 1968 Mexico City Olympics, the sports science community has maintained a high level of interest in the effects of altitude on endurance performance. At the time, competing at an elevation of 2,240 meters, many sea-level athletes experienced severe performance decrements, while athletes who had long resided at altitude demonstrated a clear advantage. This prompted scientists to systematically investigate the adaptive mechanisms of “altitude training.” However, although the early “Live High-Train High” (LHTH) model could effectively enhance red blood cell production, the inability to maintain training intensity—because maximal aerobic power output declines significantly at altitude due to reduced partial pressure of oxygen—suppressed peripheral muscular adaptations (such as mitochondrial density and capillary density).

In the 1990s, American exercise physiologists Benjamin Levine and James Stray-Gundersen proposed the revolutionary “Live High-Train Low” (LHTL) model. Its core concept is to have athletes “live” at altitudes of 2,000–2,500 meters, using continuous hypoxic exposure to stimulate red blood cell production; but “train” at altitudes below 1,200 meters to maintain near-sea-level training intensity and power output. This strategy cleverly separates the two stimuli of “hypoxic exposure” and “high-intensity training,” allowing athletes to simultaneously reap the dual dividends of hematological and neuromuscular adaptations.

1.2 Physiological Differences Between Normobaric Hypoxia and Hypobaric Hypoxia

Traditional altitude training is typically conducted at natural high-altitude locations, exposing athletes to a “hypobaric hypoxia” environment. However, with technological advances, many sports science centers and high-end training facilities now employ “normobaric hypoxia” technology, using nitrogen dilution or membrane filtration systems to reduce the fraction of inspired oxygen (FiO2) from the standard 20.9% to 15.5%–16.5% while maintaining standard atmospheric pressure (approximately 760 mmHg), simulating the hypoxic environment of 2,000–2,500 meters altitude.

It is worth examining in depth that these two hypoxic modes exhibit subtle but critical differences in physiological responses. In a hypobaric hypoxic environment, because total atmospheric pressure decreases, the reduction in alveolar oxygen partial pressure (PAO2) is more pronounced than in normobaric hypoxia, leading to a greater rise in pulmonary artery pressure and a more pronounced ventilatory response. However, recent research (such as a meta-analysis published in the Journal of Applied Physiology in 2021) indicates that, as long as the equivalent altitude is controlled within the 2,000–2,500 meter range, there is no significant difference between normobaric and hypobaric hypoxia in terms of inducing EPO secretion and red blood cell production. This provides a more convenient and more controllable alternative for athletes who cannot frequently travel to high-altitude training sites.

1.3 Why Red Cell Volume Is the “Holy Grail” of Endurance Performance

In exercise physiology, maximal oxygen uptake (VO2max) is regarded as the gold-standard indicator of endurance performance. According to the Fick principle, VO2max = Cardiac Output (Q) × Arteriovenous Oxygen Difference (a-vO2 diff). One of the core determinants of the arteriovenous oxygen difference is arterial oxygen content (CaO2), calculated as:

CaO2 = (Hb × 1.34 × SaO2) + (PaO2 × 0.003)

where Hb is hemoglobin concentration (g/dL), 1.34 is the amount of oxygen that can bind per gram of hemoglobin (mL O2/g Hb), SaO2 is arterial oxygen saturation, PaO2 is arterial partial pressure of oxygen (mmHg), and 0.003 is the solubility coefficient of dissolved oxygen in plasma.

From the formula, it is clear that hemoglobin concentration (Hb) is the largest contributing factor to arterial oxygen content. And an increase in hemoglobin concentration ultimately depends on an increase in “Red Cell Volume” (RCV). Notably, RCV growth is not merely a change in concentration but an expansion of total volume. This means that an athlete’s blood volume (BV) and plasma volume (PV) also adjust in tandem, thereby affecting blood viscosity, cardiac venous return, and thermoregulatory capacity. Therefore, how to safely and effectively increase RCV has become a core topic in endurance sports science research.

---

2. Core Mechanisms of Exercise Physiology and Biomechanics

2.1 Hypoxia Sensing: The Molecular Regulatory Hub of HIF-1α

When the human body is exposed to a hypoxic environment at 2,000–2,500 meters altitude, oxygen-sensing mechanisms in renal interstitial fibroblasts and liver cells are activated. The core of this mechanism is the “Hypoxia-Inducible Factor” (HIF), in which the HIF-1α subunit plays a critical role.

Under normoxic conditions (at sea level), intracellular prolyl hydroxylase domain enzymes (PHD) use oxygen as a substrate to hydroxylate specific proline residues (Pro402 and Pro564) on the HIF-1α protein. This modification promotes the von Hippel-Lindau (VHL) tumor suppressor protein to recognize and bind HIF-1α, subsequently directing it to the proteasome for ubiquitination and degradation. Therefore, under normoxic conditions, the half-life of intracellular HIF-1α is extremely short (approximately 5 minutes), and its concentration remains at very low levels.

However, when ambient oxygen concentration decreases (e.g., at 2,500 meters altitude, with FiO2 around 15.5%), intracellular oxygen partial pressure drops to approximately 30–40 mmHg, inhibiting PHD enzyme activity. This prevents HIF-1α from being hydroxylated and degraded, allowing it to accumulate stably in the cytoplasm and translocate to the nucleus, where it forms a heterodimer with HIF-1β (also known as ARNT). This complex then recognizes the “Hypoxia Response Element” (HRE) on the promoters of target genes, initiating the transcription of hundreds of downstream genes.

2.2 The Physiological Timing of Pulsatile EPO Secretion

Among the many target genes regulated by HIF-1α, the most critical for endurance athletes is the erythropoietin (EPO) gene. When HIF-1α binds with HIF-1β, it directly binds to the enhancer region upstream of the EPO gene, substantially increasing the transcription rate of EPO.

Notably, EPO secretion does not rise continuously but follows a “pulsatile” secretion pattern. According to a classic study published in High Altitude Medicine & Biology in 2017, when subjects moved from sea level (approximately 200 meters altitude) to 2,320 meters and resided there continuously, serum EPO concentrations exhibited the following temporal sequence:

This time series reveals the key principle of the LHTL strategy: the EPO “pulse” stimulus is concentrated in the first 48–72 hours, after which it gradually subsides due to negative feedback mechanisms (increased hemoglobin concentration → increased arterial oxygen content → increased renal oxygen tension → restored PHD activity → HIF-1α degradation). Therefore, to maximize red blood cell production, athletes should arrange high-quality recovery and nutritional support within the first 3–5 days of entering the hypoxic environment, ensuring that sufficient raw materials (iron, protein, B vitamins) are available for the hematopoietic system during the EPO peak.

2.3 The Time Delay of Erythropoiesis and RCV Expansion

The primary targets of EPO are erythroid progenitor cells in the bone marrow (BFU-E and CFU-E). Upon binding to its receptor (EPOR), EPO activates the JAK2-STAT5 signaling pathway, inhibiting apoptosis of erythroid progenitor cells and promoting their proliferation and differentiation. However, differentiation from CFU-E to mature reticulocytes released into the bloodstream requires approximately 5–7 days; reticulocytes then require an additional 2–3 days to mature into functional red blood cells.

This means that after athletes enter a Live High-Train Low environment, although serum EPO concentrations peak within 24–48 hours, the actual expansion of RCV exhibits a 7–10 day “time delay.” According to classic research data from Stray-Gundersen et al., after a four-week LHTL intervention, athletes’ RCV increased by an average of 5%–8%, with the exact magnitude depending on the following variables:

• Daily hypoxic exposure duration: 12–16 hours per day of exposure is superior to 8–10 hours.
• Residence altitude: 2,200–2,500 meters is superior to 1,800–2,000 meters.
• Individual iron storage status: Serum ferritin > 50 ng/mL is the basic threshold; > 100 ng/mL is ideal.
• Training load and recovery quality: Overtraining suppresses erythropoiesis; adequate sleep and carbohydrate intake optimize hematopoietic efficiency.

2.4 Quantitative Conversion Model of RCV Growth to VO2max

How does RCV growth translate into improvements in sea-level VO2max? We can derive this through the following mathematical model. Assume a 70 kg male endurance athlete with an initial hemoglobin concentration of 14.5 g/dL, total blood volume of 5.2 L, of which RCV is 2.4 L and plasma volume (PV) is 2.8 L.

After four weeks of LHTL, RCV increases by 6% (i.e., an increase of 144 mL), reaching 2.544 L. If plasma volume remains unchanged (in reality, it increases slightly to maintain hemorheological balance), total blood volume increases to 5.344 L. At this point, hemoglobin concentration changes approximately as follows:

Hb_new = (RCV_new × Mean Corpuscular Hemoglobin Concentration) / Total Blood Volume

Assuming the mean corpuscular hemoglobin concentration (MCHC) is approximately 34 g/dL:

• Initial total hemoglobin mass = 2,400 mL × 34 g/dL = 816 g
• Post-increase total hemoglobin mass = 2,544 mL × 34 g/dL = 864.96 g
• Hemoglobin concentration = 864.96 g / 5,344 mL ≈ 16.2 g/dL

The increase from 14.5 g/dL to 16.2 g/dL represents an approximately 11.7% increase in arterial oxygen content (CaO2). According to the Fick principle, at maximal exercise intensity, if maximal cardiac output (Qmax) and muscle oxygen extraction capacity remain unchanged, the theoretical increase in VO2max is approximately 8%–10%. However, the VO2max increases observed in actual studies typically fall between 3%–6%, because:

1. The concurrent expansion of plasma volume dilutes the rise in hemoglobin concentration.
2. Increased blood viscosity may slightly reduce cardiac output.
3. Individual variability in erythropoietic response (Low Responder vs. High Responder) is significant.

2.5 The Interaction Between Hemorheology and Exercise Economy

An increase in RCV is not “the more, the better.” When hematocrit (Hct) exceeds 55%, blood viscosity rises exponentially, increasing cardiac afterload and reducing microcirculatory perfusion, which paradoxically impairs exercise performance. Therefore, the goal of LHTL is to elevate RCV to an individual’s optimal range (typically Hct 48%–52% for males, 44%–48% for females), rather than pursuing extreme values.

Furthermore, an increased number of red blood cells also enhances the blood’s oxygen-buffering capacity. During submaximal exercise (e.g., at 75%–85% of FTP), steady-state lactate concentrations decrease due to improved oxygen delivery, allowing athletes to sustain a given power output for longer durations, or to produce higher power at the same subjective level of fatigue. This is the physiological basis for the positive effects of LHTL on “Functional Threshold Power” (FTP) and “Time to Exhaustion” (TTE).

---

3. Key Parameter Measurements and Comparative Analysis

3.1 Dose-Response Effects of Different Altitudes on EPO Secretion and RCV Growth

To precisely quantify the optimal “dose” for LHTL, we have compiled data from multiple high-quality studies in recent years for systematic comparison:

From the table, it is clear that 2,000–2,500 meters is the “sweet spot.” Below 2,000 meters, the hypoxic stimulus is insufficient to produce a significant EPO pulse; above 2,500 meters, although EPO secretion is more pronounced, the risks of sleep disturbance, decreased appetite, and impaired training recovery also increase in tandem, potentially offsetting the benefits of hematological adaptation.

3.2 Comparative Benefits: LHTL vs. LHTH vs. LLTH

This comparison table clearly presents the unique advantage of LHTL: it achieves the most critical hematological adaptation without sacrificing training quality. For mature endurance athletes who already possess a solid muscular and mitochondrial foundation, increasing RCV is often the final piece of the puzzle for breaking through performance plateaus.

3.3 Individual Variability: High Responders vs. Low Responders

Not all athletes respond equally to LHTL. Research indicates that approximately 20%–30% of athletes are “Low Responders,” with RCV increases of less than 3%. Possible factors contributing to individual variability include:

• Iron metabolism status: When ferritin < 30 ng/mL, hematopoietic raw materials are insufficient, and EPO stimulation cannot be effectively converted into red blood cell production.
• HIF-1α gene polymorphisms: Specific single nucleotide polymorphisms (SNPs) can affect the stability and transcriptional activity of HIF-1α.
• EPO receptor sensitivity: The response threshold of an individual’s bone marrow progenitor cells to EPO differs.
• Training status: In an overtraining state, inflammatory cytokines (such as IL-6, TNF-α) suppress erythropoiesis.

---

4. Periodized Training Plans and Operational Adjustment Guidelines

4.1 Overall Structure of a Four-Week LHTL Training Camp

A complete LHTL training cycle typically lasts 3–4 weeks, followed by a 1–2 week “washout period” (during which athletes may return to sea level residence while retaining some hematological benefits). The following is a four-week plan designed for amateur elites or professional athletes with at least 3 years of training experience and an FTP of 250–320W:

4.2 Sample Detailed Weekly Schedule (Using Week 2 as an Example)

Monday (Recovery Day):

• Morning: 60 minutes Z1 recovery ride (power < 55% FTP)
• Afternoon: 30 minutes light strength training (core + lower body, low intensity)
• Hypoxic exposure: 14 hours (sleep + rest time)

Tuesday (Tempo Day):

• Morning: 90 minutes Z2 endurance ride (power 56%–75% FTP)
• Afternoon: 45 minutes Z3 tempo ride (power 76%–90% FTP), placed in the latter part of the session
• Hypoxic exposure: 14 hours

Wednesday (Interval Day):

• Morning: 30 minutes Z1-Z2 warm-up → 6 × 5 minutes Z4 threshold intervals (power 91%–105% FTP), with 3 minutes Z1 recovery → 20 minutes cool-down
• Afternoon: Complete rest or 30 minutes walking
• Hypoxic exposure: 16 hours (enter hypoxic rest chamber early)

Thursday (Recovery Day):

• Morning: 45 minutes Z1 recovery ride
• Afternoon: Stretching and foam rolling
• Hypoxic exposure: 14 hours

Friday (Endurance Day):

• Morning: 120 minutes Z2 endurance ride, maintaining Z3 for the final 20 minutes
• Afternoon: 30 minutes light core training
• Hypoxic exposure: 14 hours

Saturday (Long Ride Day):

• Morning: 180–240 minutes Z2 long-distance ride (simulating the Yangmingshan Fengzhongjian or Tour of East Taiwan terrain, including 3–4 climbs at 8–12% grade)
• Afternoon: Thorough recovery, high-carbohydrate diet
• Hypoxic exposure: 12 hours

Sunday (Complete Rest or Active Recovery):

• Morning: 60 minutes Z1 very easy ride or walking
• Afternoon: Massage or contrast bath
• Hypoxic exposure: 16 hours

4.3 Heart Rate and Power Zone Comparison and Adjustment Principles

In a hypoxic environment, heart rate response during exercise is slightly higher than at sea level (approximately 3–5 bpm increase per 1,000 meters of altitude). Therefore, during LHTL, “power” should be the primary training intensity metric rather than heart rate. If heart rate must be used, adjust each zone upward by 5–8 bpm as a reference:

---

5. Race Nutrition, Environmental Adaptation, and Race-Day Strategies

5.1 Quantitative Guidelines for Erythropoietic Nutritional Support

During LHTL, the rate of red blood cell production increases substantially, and nutritional demands rise in tandem. The following are daily quantitative recommendations for nutrient intake:

Iron: 18–25 mg/day (males) / 25–30 mg/day (females). Prioritize heme iron (animal sources such as lean red meat, duck blood, clams), with an absorption rate of 15%–35%; non-heme iron (spinach, black beans, red amaranth) should be paired with vitamin C to enhance absorption. It is recommended to begin supplementation 2 weeks before entering the hypoxic environment to ensure ferritin > 50 ng/mL.

Protein: 1.6–2.0 g/kg body weight per day, with at least 30% from high biological value proteins (whey, eggs, lean beef). The red blood cell membrane is primarily composed of phospholipids and proteins; an adequate supply of amino acids is critical for red blood cell membrane integrity.

Vitamin B12 and Folate: At least 2.4 μg of B12 and 400 μg of folate per day. These two vitamins are essential coenzymes for DNA synthesis and red blood cell maturation; deficiency can lead to megaloblastic anemia, severely undermining the erythropoietic effects of LHTL.

Fluids and Electrolytes: Hypoxic environments increase respiratory rate, leading to greater insensible water loss. Daily fluid intake should reach 35–45 mL/kg body weight, with appropriate sodium supplementation (approximately 1–2 g of sodium is lost per 1,000 mL of sweat).

5.2 The “Coming Down from Altitude” Strategy Before Competition

After an LHTL training camp, athletes should not immediately compete in important events. The “optimal performance window” for hematological adaptations typically occurs 7–21 days after returning to sea level. The following is a specific timeline:

• Days 1–3: Complete rest or very light recovery rides (Z1), allowing hemorheology to readjust.
• Days 4–7: Gradually resume training volume, incorporating 1–2 Z3-Z4 intensity stimuli to reawaken neuromuscular pathways.
• Days 8–14: Perform 1–2 high-quality threshold interval sessions and 1 long Z2 ride to confirm performance levels.
• Days 15–21: Taper, reducing training volume to 60%–70% of normal while maintaining intensity but shortening duration, in preparation for the main event.

Using classic Taiwanese events as examples: if the target is the “Eastbound Wuling” (elevation 3,275 m, total length 55 km, average grade 5.5%), it is recommended to compete 12–16 days after LHTL concludes, when the RCV dividend is still present and neuromuscular adaptations have fully recovered. If the target is the “One-Day Taipei-Kaohsiung” (360 km flat course), the event can be scheduled 7–10 days after LHTL concludes, leveraging the thermoregulatory advantage and enhanced endurance provided by blood volume expansion.

5.3 Immediate Response for High-Altitude Races

If the race itself takes place at elevations above 2,000 meters (such as Wuling or certain segments of KONA), athletes need to pay additional attention to:

• Arrival time: Arrive at the race venue 3–5 days in advance, but engage only in light activity during the first 24 hours to allow the body to complete acute ventilatory adaptation.
• Race pacing: At high altitude, VO2max decreases by 10%–20%, and FTP decreases by approximately 8%–12%. It is recommended to lower power targets by 8%–10%, using heart rate and RPE as the primary pacing metrics.
• Nutrition strategy: Gastric emptying slows at altitude; it is recommended to consume 60–90 g of carbohydrates per hour (primarily as 6–8% isotonic solutions) and increase fluid intake by 10%–15%.

---

6. Common Operational Mistakes and Scientific Myth-Busting

6.1 Myth 1: Training Intensity Should Be Increased Simultaneously During LHTL

Debunking: This is the most common and most dangerous misconception. The core value of LHTL lies in the separation of “hypoxic exposure” and “high-intensity training.” In a hypoxic environment, the body is already under additional physiological stress (increased ventilation, sympathetic activation, elevated oxidative stress). If training intensity is simultaneously increased, it leads to inadequate recovery, overtraining, and immunosuppression. The correct approach is: during LHTL, training volume can be maintained at 90%–100% of sea-level values, but intensity distribution should emphasize Z1-Z2 (comprising 60%–70% of total training time). Z3-Z4 sessions should be scheduled during periods “after training when returning to lower altitude,” and should not exceed 2–3 sessions per week.

6.2 Myth 2: More EPO Secretion Is Always Better, and Higher Altitude Is More Effective

Debunking: As previously discussed, EPO secretion is pulsatile and subject to negative feedback regulation. Excessively high altitudes (> 3,000 m), while inducing a more pronounced EPO response, simultaneously lead to:

1. Significantly impaired sleep quality (hypoxia-induced central sleep apnea).
2. Appetite suppression, inadequate caloric intake, and increased risk of muscle breakdown.
3. Substantially increased oxidative stress, potentially damaging red blood cell membrane stability.
4. Excessive elevation of pulmonary artery pressure, increasing right ventricular workload.

Scientific evidence shows that the “effective hypoxic dose” of 2,200–2,500 meters is already sufficient to induce maximal RCV growth; increasing altitude further only adds risk.

6.3 Myth 3: The Effects of LHTL Can Be Maintained Permanently

Debunking: The lifespan of red blood cells is approximately 120 days, but the RCV gained from LHTL gradually dissipates at a rate of approximately 1% per week after returning to sea level, with the effect completely disappearing after approximately 3–4 weeks. Therefore, LHTL should be viewed as a “phase-specific enhancement tool before a competition cycle,” not a continuous training modality. It is recommended to schedule 2–3 LHTL training camps per year, with at least 8–10 weeks between camps, to ensure the body has sufficient time to recover and maintain training quality.

6.4 Myth 4: Using a Hypoxic Rest Chamber Alone Provides All the Benefits

Debunking: Hypoxic rest chambers (such as the Hypoxico Tent) can indeed provide a stable normobaric hypoxic environment, but their effectiveness depends on “daily exposure duration” and “total number of days.” If used only during sleep (approximately 8 hours), daily hypoxic exposure falls short of 12 hours, and RCV growth is substantially diminished. Ideally, athletes should extend hypoxic exposure into daytime rest periods (such as reading, watching videos, or napping), accumulating 14–16 hours per day. Furthermore, a hypoxic rest chamber cannot replace the critical component of “returning to lower altitude immediately after training.” Therefore, if training at home, it is essential to confirm that the oxygen concentration in the training area genuinely differs from that in the rest area.

6.5 Myth 5: LHTL Is Equivalent to Blood Doping and Constitutes Doping

Debunking: LHTL is a legal training method explicitly permitted by the International Olympic Committee (IOC) and the World Anti-Doping Agency (WADA). It stimulates the body’s own physiological adaptations through exposure to natural or simulated environments, which is fundamentally different from the illegal use of EPO injections or blood doping. However, athletes should be aware that changes in blood parameters during LHTL (such as elevated hematocrit) may trigger abnormal alerts in the Athlete Biological Passport (ABP). Therefore, it is recommended to conduct LHTL under the supervision of coaches and a sports science team, with complete documentation of training and exposure logs.

---

7. Expert FAQ

Q1: I am an amateur cyclist with an FTP of approximately 220W. Is LHTL training suitable for me?

In-depth Answer: The benefit of LHTL lies in “breaking through already well-developed physiological adaptations.” If you have fewer than 3 years of training experience, or your current FTP is below 3.5 W/kg (male) / 3.0 W/kg (female), it is recommended to first focus on building foundational aerobic capacity and refining technique at sea level. The reason is that the RCV increase from LHTL (5%–8%) translates to a VO2max improvement of approximately 3%–6%. If your VO2max can still improve by 5%–10% per year through conventional training, the marginal benefit of LHTL is relatively limited. Conversely, if you are in a training plateau phase, with conventional training improvements below 2%, LHTL is an effective tool for breaking through the bottleneck. Additionally, LHTL requires significant time and financial investment (hypoxic equipment or accommodation, nutritional monitoring, blood testing) and should only be undertaken when resources permit and scientific supervision is available.

Q2: How should fatigue and recovery status be monitored during LHTL?

In-depth Answer: In addition to traditional resting heart rate (HRrest) and body weight monitoring, the following indicators are particularly recommended during LHTL:

1. Sleep blood oxygen saturation (SpO2): Use wearable devices to monitor average nocturnal SpO2. If it falls below 85% and is accompanied by frequent awakenings, consider reducing the hypoxic concentration or shortening exposure duration.
2. Training pulse oximetry (Training SpO2): Measure SpO2 during Z3-Z4 sessions. If it falls below 88%, the hypoxic load is too high; reduce intensity or return to a lower altitude for training.
3. Session RPE (sRPE) and Profile of Mood States (POMS): Record daily fatigue (0–10 scale) and mood tension. If fatigue ≥ 7 for 3 consecutive days accompanied by rising mood tension, schedule a complete rest day.
4. Blood markers: It is recommended to test hematocrit (Hct), hemoglobin (Hb), reticulocyte count, and ferritin before LHTL, at the end of Week 2, and at the end of Week 4. Reticulocyte count is the best early indicator that “erythropoiesis is underway,” typically beginning to rise 5–7 days after the EPO peak.

Q3: Do female athletes need to pay special attention to the effects of the menstrual cycle during LHTL?

In-depth Answer: Yes. Iron metabolism in female athletes is closely linked to the menstrual cycle. Iron loss during menstruation (days 1–5) is approximately 15–25 mg, which significantly affects the supply of hematopoietic raw materials. The following strategies are recommended:

1. Schedule the start of the LHTL camp during the “late follicular phase to ovulation” (approximately days 8–14) of the menstrual cycle, when estrogen levels are rising, iron absorption efficiency is better, and subjective well-being is typically improved.
2. During menstruation, increase daily iron intake to 30–35 mg, paired with 500 mg of vitamin C to promote absorption.
3. If using oral contraceptives, note that they may affect HIF-1α stability; some studies suggest that oral contraceptive users may have a reduced response to LHTL.