Methods, cont'

1
A randomized, placebo-controlled study of the
influence of instant-release metformin on
response to clomiphene citrate and time to
conception in polycystic ovary syndromeWilliams
CD1, Pastore LM2, Shelly W2, Bailey AP2, Baras
D2, Bateman B11 Reproductive Medicine Surgery
Center of Virginia, PLC, Charlottesville, VA, 2
Department of Obstetrics Gynecology, University
of Virginia, Charlottesville, VA

• Methods, cont.
• Mid-luteal progesterone was measured, and the
  patient was considered ovulatory with a level
  5ng/mL. However, CC was increased by 50mg to a
  maximum dose of 200mg until optimal ovulation was
  documented by a progesterone level gt15ng/mL.
• Once optimally ovulatory, subjects remained in
  treatment arm until conception or up to 6 cycles.
  Subjects who did not become optimally ovulatory
  on 200mg CC were unblinded. CC P subjects were
  allowed to cross-over to CC M. CC M subjects
  were withdrawn from further study after 6 cycles.
• With positive pregnancy test, an ultrasound was
  performed between 6-7 weeks at which time
  metformin or placebo was discontinued.
• Statistical Analyses
• Univariate analyses Student-t, Wilcoxon rank
  sum, survival methods, and log rank tests

Background Polycystic ovary syndrome (PCOS) is
the most common endocrine disorder of
reproductive age women and is the most common
endocrine cause of infertility (Dunaif 92). 1
In some studies, adding metformin to CC has
been shown to improve ovulation rates in PCOS
patients who are resistant to CC (Nestler 98,
Vandermolen 01) but in other studies, no benefit
was demonstrated (Legro 07, Moll 06). 2,3,4,5
It has been postulated that the use of
extended-release metformin may not be as
efficacious in women with PCOS (Legro 07).
4 The investigators hypothesized that starting
instant-release metformin concurrently with CC
would improve ovulatory response and reduce the
time to conception compared to the use of CC
alone.

• References
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  eds. The Polycystic Ovary Syndrome. Cambridge
  Blackwell Scientific, 1992.
• Zawedzki JK, Dunaif A. Diagnostic criteria for
  polycystic ovary syndrome towards a rational
  approach. In Dunaif A, Givens JR, Haseltine F,
  Merriam GR, eds. The Polycystic Ovary Syndrome.
  Cambridge Blackwell Scientific, 1992 377-84.
• Franks S. Polycystic Ovary Syndrome. The New
  England Journal of Medicine 1995 333(13)
  853-861.
• Fauser BC. Revised 2003 consensus on diagnostic
  criteria and long-term health risks related to
  polycystic ovary syndrome (PCOS). The Rotterdam
  ESHRE/ASRM-sponsored PCOS consensus workshop
  group. Human Reproduction 2004 19(1) 41-47.
• Legro R, Finegood D, Dunaif A. A fasting glucose
  to insulin ratio is a useful measure of insulin
  sensitivity in women with polycystic ovary
  syndrome. Journal of Clinical Endocrinology and
  Metabolism 1998 83(8) 2694-2698.
• Dahlgren E, Johansson S, Lindstedt G, et al.
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  resected in 1956 to 1965 a long-term follow-up
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• Freedman DS, Jacobsen SJ, Barboriak JJ,
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• Dahlgren E, Janson PO, Johansson S, et al.
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• Hartz AJ, Rupley DC, Rimm AA. The association of
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• Sellers TA, Kushi LH, Potter JD, Kaye SA, Nelson
  CL, McGovern PG, et al. Effect of family
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  cancer. New England Journal of Medicine 1992
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• Lapidus L, Helgesson O, Merck C, Bjorntorp P.
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  361-368.
• Schapira DV, Kumar NB, Lyman GH, Cavanagh D,
  Roberts WS, LaPolla J. Upper-body fat
  distribution and endometrial cancer risk. Journal
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• Regan L, Owen EJ, Jacobs HS. Hypersecretion of
  luteinising hormone, infertility, and
  miscarriage. Lancet 1990 336 1141-1144.
• Homburg R, Armar NA, Eshel A, Adams J, Jacobs HS.
  Influence of serum luteinising hormone
  concentrations on ovulation, conception, and
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  syndrome. British Medical Journal 1988 297
  1024-1026.
• Watson H, Kiddy DS, Hamilton-Fairley D, et al.
  Human Reproduction 1993 8(6) 829-833.
• Knudsen UB, Hansen V, Juul S, Secher NJ.
  Prognosis of a new pregnancy following previous
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  1991 39 31-36.

Figure 1. Rate of Ovulation with and without
Metformin

• Objective
• To evaluate the influence of instant-release
  metforrmin hydrochloride (M) on the response to
  clomiphene citrate (CC) in women with polycystic
  ovary syndrome who are attempting to conceive.
• To evaluate whether participants who fail to
  ovulate at the 200 mg dose of CC alone would
  ovulate once metformin was added to the
  treatment.
• Methods
• The population studied was comprised of n55
  women. This was a triple-blind design.
• Enrollment Criteria
• Inclusion criteria were a) age 18-45 years, b)
  diagnosis of PCOS, as confirmed by normal TSH,
  prolactin and 17-hydroxyprogesterone (lt200
  ng/dL) a 2-hr glucose tolerance test with a
  2-hour value of lt200 mg/dL or a normal hemoglobin
  A1C oligoovulation (gt35 day menstrual cycles
  averaged over the previous year) or amenorrhea
  clinical hyperandrogenemia (acne and/or
  hirsutism) or elevated serum androgen levels
  (total and/or free testosterone levels or DHEAS)
  if no clinical signs of hyperandrogenism , c)
  desired pregnancy, and d) not taking metformin or
  any other medication that might influence the
  reproductive system.
• Exclusion criteria were a) use of metformin in
  the prior 60 days, b) abnormal liver or kidney
  function tests, c) prior failure to ovulate on
  clomid 200mg, or d) intolerance to metformin. The
  Human Investigation Committee of the University
  of Virginia approved this protocol (10268).
• Protocol
• All participants completed a demographics and
  behavior questionnaire.
• Randomized into Group A- CC placebo (CC P),
  Group B- CC metformin (CC M)
• CC 50mg daily on cycle days 5-9 given to all
  subjects. Placebo or metformin 500mg was given
  three times daily with meals, increasing from
  once-daily to three times daily dosing over three
  weeks.

Results
Figure 2. Rate of Conception with and without
Metformin
Table 2. Number of blinded, ovulatory cycles
prior to conception
Conclusions

• The 54.1 pregnancy rate in unblinded, ovulatory
  women on CC M is higher than previously
  reported34, possibly due to a greater efficacy of
  instant-release metformin over the
  extended-release formulation.
• Among unblinded, nonovulatory women who did not
  respond to 200mg CC, 64 were in CC P. After
  cross-over of these subjects to CC M, 67
  became ovulatory and 50 conceived. This
  suggests that instant-release metformin may
  sensitize nonresponders to high-dose CC.
• 40 of ovulatory women in CC P conceived,
  compared to 70.6 of ovulatory women in CC M.
• Time to conception for ovulatory women in CC M
  was significantly shorter than for ovulatory
  women in CC P.
• Acknowledgements
• The Authors would like to thank Mir Siadaty, MD,
  MPH, for his statistical assistance and Jody
  Halloran and Kathy Watson, RN, for their
  assistance with study coordination.

Table 1. Demographic and Behavioral Factors
between Groups