Clinical effects of adding DHEA to the pill

Transcription

1 Clinical effects of adding DHEA to the pill Roumen FJME, van Wijck A, Zimmerman XY, Beekman L, ter Kuile MM, Coelingh Bennink HJT Atrium Medical Center Parkstad, Heerlen Leiden University Medical Center Pantarhei Bioscience

2 Well-being, mood and Reported effects are contradictory A placebo-controlled, double-blind study in 150 sterilized women (or sterilized partner) demonstrated a subtle increase of irritability during COC use, more noticeable in Edinburgh women. COC (and placebo!) resulted in a slight increase of depression in Edinburgh and Manila, POP in a reduction (Graham C et al 1995)

3 Well-being, mood and Reported effects are contradictory A placebo-controlled, double-blind study in 150 sterilized women (or sterilized partner) demonstrated a subtle increase of irritability during COC use, more noticeable in Edinburgh women. COC (and placebo!) resulted in a slight increase of depression in Edinburgh and Manila, POP in a reduction (Graham C et al 1995) A community-based prospective study in 107 healthy, sexually active, pill starters demonstrated, that adverse effects on mood (33%) and sexuality (8%) were important factors in discontinuation and switching of COCs (Sanders S et al 2001)

4 Well-being, mood and Reported effects are contradictory In a nested case-control study within a community-based cohort of 976 premenopausal women in Massachusetts, COCs did not influence premenstrual mood in most women. 16.3% of women reported COC-related premenstrual mood deterioration, and 12.3% improvement. Premenstrual mood was most likely to deteriorate in women with a history of depression, and to improve in women with earlyonset premenstrual mood disturbance or dysmenorrhea (Joffe H et al 2003)

5 Well-being, mood and Reported effects are contradictory In a multi-center, community-based study in 1716 sexually active pill starters, most women reported no changes in headaches, weight, moodiness, and sexual satisfaction. 57% of the women discontinued the COC within 6 months. The most important factor leading to COC discontinuation was logistics: difficulty in obtaining more pills and in using the pills correctly (45.5%). 33.8% of subjects discontinued the COC prematurely for side effects, especially increased headaches or moodiness (Westhoff C et al 2007)

6 Well-being, mood and In conclusion: there is large variability in the direction of mood change during pill use: some women report mood disturbances with the pill, other women report no change or an improved mood

7 Well-being, mood and In conclusion: there is large variability in the direction of mood change during pill use: some women report mood disturbances with the pill, other women report no change or an improved mood Clinical experience: a certain subgroup of women do report significant mood disturbances due to their COC use

8 Negative effects of on androgens Estrogens and progestogens in the pill may reduce the bio-availability of androgens through Suppression of ovarian androgen production (50%) Increase of SHBG levels Increase of DHEA-S binding albumin

9 Mood and androgen levels Generally, there is a positive relationship between androgen levels and well-being in women (Cawood and Bancroft 1996)

10 Mood and androgen levels Generally, there is a positive relationship between androgen levels and well-being in women (Cawood and Bancroft 1996) However, sensitivity of women to changes in androgen levels is variable

11 Mood and androgen levels Generally, there is a positive relationship between androgen levels and well-being in women (Cawood and Bancroft 1996) However, sensitivity of women to changes in androgen levels is variable Variability also depends on the type of pill, type of P, and dosage EE: N/EE25 pill less reduction in T and FT than N/EE35 pill, and more improvement in premenstrual mood, but no correlation between changes in androgen levels and mood (Greco et al, 2007)

12 ARC-MOOD Primary objective to evaluate the effect of concomitant treatment with DHEA on mood disturbances during pill use

13 ARC-MOOD Secondary objectives To assess the general effects on well-being To assess satisfaction and health related quality of life

14 ARC-MOOD Inclusion criteria Women using the pill for at least 3 months prior to screening and aged years (inclusive) Regular menstrual cycles (24-35 days) prior to last start of pill use Body mass index between ( ) 18 and ( ) 35 kg/m 2 Good physical and mental health Willing to give informed consent in writing Report of mood disturbances, and attributing this to pill use as evidenced by an in depth interview

15 ARC-MOOD In depth interview Independently performed by two investigators Clear association between start complaints and start pill use More complaints during pill intake, less complaints during pill-free week

16 ARC-MOOD Exclusion criteria Androgen therapy during the 6 months prior to screening Use of other than oral application routes of hormonal contraception during the 3-6 months prior to screening History of or current psychiatric disorder not relatedto the use of the pill Use of antidepressant medication prior to screening

17 ARC-MOOD Study design (1) N=1 trial, is powerful means to detect causeeffect relationships 6 women stay on own pill throughout study 6 consecutive cycles Double-blind, randomized DHEA 50 mg vs placebo (3 cycles each)

18 ARC-MOOD Study design (2) BBABAA BABABA ABABAB ABBABA AABABB BAABAB A = placebo; B = DHEA 6 women randomly allocated to 1 of 14 possible treatment sequences Constraints: Each treatment occurs 3x Maximally 2 consecutive administrations of the same treatment

19 ARC-MOOD Primary endpoints Daily index level of mood: In what kind of mood have you been in the past 24 hours? 5 points scale (1 = very bad, 5 = very good) 21 daily scores during each treatment Hypothesis: DHEA > placebo Test statistics: differences between means cycles B and cycles A SCRT software (Single-Case Randomization Tests), version 1.1 (Onghena & Van Damme, 1994)

20 ARC-MOOD Subject characteristics Subject Age COC type Duration COC use (years) Number of COC switch DSRP/20EE LNG/ EE LNG/30EE LNG/30EE DSRP/30EE DSRP/30EE 10 5 (incl. Mirena) 2 (incl. Mirena)

21 ARC-MOOD Results (1)

22 ARC-MOOD Results (2)

23 ARC-MOOD Results (3)

24 ARC-MOOD Results (4)

25 ARC-MOOD Results (5)

26 ARC-MOOD Results (6)

27 ARC-MOOD Summary of results No difference in daily mood ratings between DHEA and placebo in pill users

28 ARC-MOOD Summary of results No difference in daily mood ratings between DHEA and placebo In subject 2 (Trinordiol) mood ratings with placebo even better

29 ARC-MOOD Discussion Mood is dependent from many psychosocial circumstances We never know the real influence of these variables in individuals

30 ARC-MOOD Discussion Adequate selection of subjects? Basic mood score was not low in most ARC-MOOD subjects In-depth interview ARC-MOOD preferably by psychologist? Select subjects who discontinued pill for mood disturbances? Select subjects on androgen level data?

31 ARC-MOOD Discussion Adequate selection of subjects? Basic mood score was not low in most ARC-MOOD subjects In-depth interview ARC-MOOD preferably by psychologist? Select subjects who discontinued pill for mood disturbances? Select subjects on androgen level data? Adequate design? DHEA use during one cycle too short? Three months DHEA vs three months placebo design better?

32 ARC-MOOD Discussion Is it really T insufficiency that causes mood suppression during pill use, or is the loss of peri-ovulatory ups and premenstrual downs, leading to mood equalization, more important?

33 Thank you for your attention!