Clinical trial NCT01944306: Obesity and Oral Contraceptive Failure
Official title: Prenatal Growth Programs Oral Contraceptive Metabolism and Effectiveness
Study type: OBSERVATIONAL
Overall status: TERMINATED
Conditions: Contraception
Fetal Growth Retardation
Infant, Small for Gestational Age
Obesity
Keywords: Pharmacokinetics
Pharmacology, Clinical
Drug Efficacy
Drug Failure
Contraceptive Agents
Lead sponsor: Oregon Health and Science University
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2013-09-17
Enrollment: 26
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Reproductive-aged, ovulatory women seeking to initiate contraception with combined oral contraceptives will be recruited from the female population of the Portland, OR area. Subjects must have access to their birth weight record. Enrollment will be confined to women who have not used a hormonal contraceptive method for 30 days or more prior to enrollment.

Brief summary: Contraceptive failure is the primary cause of unintended pregnancy in the United States. With obesity rates at epidemic proportions, any association between obesity and strategies that prevent undesired pregnancies constitutes a significant public health and economic concern. Evidence from recent epidemiological studies and our preliminary data (sub-therapeutic levels of steroid hormones due to drug clearance and half-life) suggest that obesity reduces oral contraceptive efficacy. Furthermore, preliminary analysis suggested that a sub-group of obese women, defined by their own birth weight, are at higher risk of contraceptive failure. Further studies are necessary to investigate whether birth weight, a surrogate marker of in utero growth restriction, is a useful diagnostic marker for the identification of women prone to contraceptive failure. Such an understanding is critical to finding a contraceptive strategy with better efficacy for these women.

The overall goal of this project is to test pharmacokinetics of oral contraceptive agents in obese women with low birth weight and compare to obese women with normal birth weight. The main hypothesis for this proposal is that an adverse in utero environment programs the expression and function of enzymes and transporters that underlie pharmacokinetics of oral contraceptives, and leads to contraceptive failure.

Reproductive-aged, ovulatory women of obese BMI \>30 kg/m2 with normal birth weight (5.5-8 lbs; n=10) and low birth weight (\<5.5 lbs; n=10), will be placed on oral contraceptives for 1 month. At several key time points, synthetic steroid pharmacokinetics, gonadotropins (luteinizing hormone, follicle-stimulating hormone) and ovarian hormone levels (estradiol, progesterone) will be monitored.


Eligibility criteria: Inclusion Criteria:

* age 18 to 35.
* single progesterone level of 3 ng/mL or greater during the luteal phase (days 18 to 25) in the menstrual cycle prior to dosing with oral contraceptives.

Exclusion Criteria:

* absolute/relative contraindications to ethinyl estradiol and levonorgestrel.
* impaired liver function.
* history of deep venous thrombosis.
* hypertension (\> 140/90).
* diabetes with vascular changes.
* migraines with aura or neurological changes.
* history of myocardial infarction, pulmonary embolus, stroke or breast cancer.
* anemia (hematocrit \< 36%).
* actively seeking or involved in a weight loss program (must be weight stable)
* pregnancy, breastfeeding, or seeking pregnancy.
* diagnosis of Polycystic Ovarian Syndrome.
* recent (4 week) use of hormonal contraceptives (patch or ring included), intrauterine, or implantable hormonal contraception.
* DepoProvera use within six months.
* current use of drugs that interfere with metabolism of sex steroids.
* smokers.
* uncontrolled thyroid dysfunction.

Primary outcomes:
measure: Measure pharmacokinetic parameters of oral contraceptives including drug clearance.
timeFrame: on day 21 of oral contraceptive use
Secondary outcomes:
measure: Measure levels of gonadotropins and ovarian hormones
timeFrame: Days 21-25 of oral contraceptive use
Other outcomes:
Locations:
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
Study officials:
affiliation: Oregon Health and Science University
name: Ganesh Cherala, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Edelman AB, Carlson NE, Cherala G, Munar MY, Stouffer RL, Cameron JL, Stanczyk FZ, Jensen JT. Impact of obesity on oral contraceptive pharmacokinetics and hypothalamic-pituitary-ovarian activity. Contraception. 2009 Aug;80(2):119-27. doi: 10.1016/j.contraception.2009.04.011. Epub 2009 Jun 4.
citation: Cherala G, Thornburg K, Edelman A. Birthweight and cytochrome P4503A4/5 activity in obese women. Br J Clin Pharmacol. 2013 Jan;75(1):275-6. doi: 10.1111/j.1365-2125.2012.04309.x. No abstract available.
citation: Edelman AB, Cherala G, Munar MY, Dubois B, McInnis M, Stanczyk FZ, Jensen JT. Prolonged monitoring of ethinyl estradiol and levonorgestrel levels confirms an altered pharmacokinetic profile in obese oral contraceptives users. Contraception. 2013 Feb;87(2):220-6. doi: 10.1016/j.contraception.2012.10.008. Epub 2012 Nov 12.
citation: Edelman A, Cherala G, Lim JY, Jensen JT. Contraceptive failures in overweight and obese combined hormonal contraceptive users. Obstet Gynecol. 2013 Jul;122(1):158-159. doi: 10.1097/AOG.0b013e3182995811. No abstract available.