Joseph B Stanford, MD Karen C Schliep, PhD Ahmad O Hammoud, MD. Enrique Schisterman, PhD Sunni Mumford, PhD Christy Porucznik, PhD

Transcription

1 Joseph B Stanford, MD Karen C Schliep, PhD Ahmad O Hammoud, MD Enrique Schisterman, PhD Sunni Mumford, PhD Christy Porucznik, PhD

2 Menstrual cycle ovulatory disorders range from luteal phase deficiency (LPD) to more advanced cases of anovulation. Alterations in life style (exercise, diet, and stress) and abnormal endocrine dynamics are known to cause anovulation; however, their role in milder menstrual cycle phenotypes such as LPD is less known.

3 Clinically, LPD may be associated with: 1. abnormal luteal phase progesterone and estradiol (E2) production 2. shortening of the menstrual cycle (by shortening of the luteal phase) 3. premenstrual spotting or bleeding 4. pregnancy related disorders such as infertility (via impairment of endometrial development) and early pregnancy loss.

4 While LPD is thought to occur in 3-20% of women who are infertile and in 25-60% of women with recurrent spontaneous abortion, data also suggest that 6-10% of women with normal fertility demonstrate an inadequate luteal phase. There is a need, thus, to better understand normal variations in the menstrual cycle phases and in variations that could be pathologic.

5 Assess luteal phase function in the BioCycle Study by determining cycles with: 1. Short luteal phases (< 10 days in length) 2. Incidence of premature luteinization (evidenced by a late follicular rise in progesterone before ovulation) 3. Premenstrual spotting 4. Abnormal luteal phase progesterone

6 1. Some normal cycling women express evidence of subtle menstrual cycle disorders manifested as LPD. 2. Various demographic, lifestyle, environmental, and nutritional factors increase the incidence of LPD.

7 BioCycle Study ( ): Followed 259 women from NY region for two menstrual cycles Inclusion: Ages Regularly menstruating Exclusion: Conditions known to affect menstrual cycle function Self-reported over- or underweight or unusual diet Strong compliance: 250 completed two cycles; 9 completed one cycle

8 BioCycle women with cycles of known length (as determined by daily records of menstrual bleeding) who reached peak fertility via Clearplan fertility monitor (based on E3G and LH in urine) OR who reached an LH peak serum surge > 19 ng/ml (for women not peaking via the monitor or with cycle lengths 30 days) n=241 women, 406 cycles

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10 Observed day of ovulation (i.e., urine or serum LH surge + 1 day) was used to classify visits into correct cycle phase categories. Cycle length was defined as number of days between menstrual bleeding. Day 1 of the cycle was defined as menstruating by 4pm on that day (after confirming 2 consecutive days of bleeding). Follicular length: Day 1 of bleeding through day of ovulation. Luteal length: Day after ovulation through last day of cycle.

11 Based on previous research, we defined LPD in 5 unique ways: 1. Luteal phase duration < 10 days in length. 2. Deficient luteal phase progesterone production via AUC analysis (i.e., lowest quintile). 3. Deficient luteal phase progesterone production via cutpoint (i.e., 5 ng/ml for all 3 luteal visits). 4. Progesterone 2ng/mL before ovulation. 5. Premenstrual spotting (defined as 2 consecutive days of menstrual bleeding).

12 Data on potential confounders were collected by anthropometric measurement (height and weight), questionnaires (lifestyle, physical activity, and reproductive history), or interview (demographic and dietary information).

13 Descriptive statistics by LPD for all 3 definitions were computed for potential confounding variables and menstrual cycle characteristics (i.e., overall cycle length, premenstrual spotting, and geometric mean hormone levels) taking into account multiple cycles from the same women.

14 Nonlinear harmonic models were used to assess the association between LPD and hormonal patterns. All models were adjusted for age, BMI, race. We used centered models for mean and amplitude and non-centered models for phase shift assessment.

15 Luteal phase < 10 days Luteal progesterone <5ng/mL Lowest quintile of luteal AUC progesterone (<54.5 ng/ml) n=39 cycles n=35 cycles n=82 cycles

16 n=16 cycles Luteal phase length <10 days n=6 cycles Luteal phase P <5 ng/ml n=19 Luteal phase AUC P <54.5 ng/ml n=30 n=328 cycles n=17 cycles

17 Luteal phase < 10 days Significantly (P<0.05) associated with white race; trend (P<0.10) towards younger age, increased fiber intake, and high physical activity. Luteal phase progesterone <5ng/mL Significantly (P<0.05) associated with younger age and decreased sleep; trend (P<0.10) towards never having been pregnant and increased fiber intake. Luteal phase AUC progesterone <54.5 ng/ml Significantly (P<0.05) associated with younger age and never having been pregnant; trend toward decreased alcohol intake.

18 Estradiol Luteal phase < 10 days Luteal AUC progesterone < 54.5 ng/ml Luteal progesterone < 5 ng/ml Mean P=0.008

19 LH Luteal phase < 10 days Luteal AUC progesterone < 54.5 Luteal progesterone < 5 ng/ml Amplitude P=0.12

20 FSH Luteal phase < 10 days Luteal AUC progesterone < 54.5 Luteal progesterone < 5 ng/ml Mean P<0.001

21 Progesterone Luteal phase < 10 days Mean P=0.02 Amplitude P=0.03

22 Findings suggest that normal cycling women do express evidence of subtle menstrual cycle disorders manifested as LPD. Age, race, sleep, and dietary factors (e.g., fiber intake) may be associated with LPD in normal cycling women. LPD may express itself in different ways, potentially through different mechanisms.

23 Decreased E2 across the cycle significantly associated with deficient luteal progesterone production. Increased FSH significantly associated with short luteal phase duration and deficient luteal progesterone production. Decreased progesterone significantly associated with short luteal phase duration.

24 Need for a better diagnostic test to assess luteal phase insufficiency. LPD, an independent entity causing infertility, has not been proven. While we show here that LPD is present in normal cycling women, we cannot infer if it is pathological in regards to fertility.

25 Further research is needed to assess what factors influence LPD, so that preventive strategies via lifestyle modifications or minimally invasive therapeutic treatments might be implemented for women suffering from reproductive disorders due to LPD.

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