The use of Kliogest as addback in patients on Zoladex treatment for endometriosis

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The use of Kliogest as add-back in patients on
Zoladex treatment for endometriosis

• Henk R. Franke, Peter HM. vd Weijer, Ton MM.
  Pennings and Jan M. vd Mooren

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Design of the study

• prospective
• randomized
• placebo controlled
• double blind
• multicentered

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Medication

• GnRH agonist Zoladex depot, 3.6 mg goserelin
  acetate
• HRT Kliogest, continuous combined 2 mg
  estradiol and 1 mg norethisterone acetate
• Both drugs during 24 weeks

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Aims of the study

• GnRH-a plus HRT reduces side effects of GnRH-a
  treatment such as estrogen deficiency symptoms
  and bone loss
• without compromising the efficacy of GnRH-a
  treatment on endometriosis

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Inclusion criteria

• age 18-50 years
• laparoscopically diagnosed endometriosis, AFS-R
  score of 2 or more
• informed consent

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Baseline Characteristics
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Main outcome measures

• laparoscopy
• bone mineral density
• subjective side effects

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Laparoscopy

• within 3 months before initiation of treatment
• AFS-R score 2 or more
• no attempt for reduction of endometriotic lesions
  was performed

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Endometriosis Response
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Follow-up laparoscopy

• between 4 and 6 weeks after final goserelin
  injection
• remaining endometriotic lesions were removed by
  laservaporisation, electrocautery or ultracision
• one drop out, no follow-up laparoscopy

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Lumbar spine BMD
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Kupperman index

• hot flushes
• sweats
• sleep
• nervousness
• depression
• vertigo

• asthenia
• arthralgia
• headaches
• palpitations
• vaginal dryness

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Subjective Side Effects
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Discussion

• GnRH-a treatment results in a deleterious effect
  to bone microstructure of trabecular bone
• the adverse effects on the bone microstructure
  will not be reversed completely (Compston et al,
  1995)
• increased future fracture risk

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Draw backs long term GnRH-a treatment

• limitation to 6 months
• BMD loss, 1 per 4 weeks
• estrogen deficiency symptoms

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GnRH-a plus add-back

• reduces the impact of treatment on BMD
• relieves estrogen deficiency symptoms
• causes no reduction in the efficacy of GnRH-a
• and so extend the treatment boundaries

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Take Home Messages

• GnRH-a plus HRT is effective and safe (no bone
  loss)
• Extension of GnRH-a plus HRT treatment for more
  than 24 weeks possible
• High patients compliance in longterm treatment

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The decision to use add-back is yours
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Endometriosis

• Endometriosis is the presence of functional
  endometrial tissue (glands and stroma) outside
  the uterine (endometrial) cavity

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Symptoms

• pelvic pain
• infertility
• dysmenorrhea
• menorrhagia/abnormal bleeding
• dyspareunia
• backache

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Incidence

• about 10 of all women of reproductive age
• 20-40 of infertile women
• the second most common gynecological condition
  after fibroids

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Pathogenesis

• genetic predisposition, sisters of a sufferer
  have a 7-times increased risk compared with
  unrelated women
• retrograde menstruation
• abnormality in the immune system
• lymphatic or circulatory involvement

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Diagnosis-Laparoscopy

• laparoscopy is generally used to confirm
  diagnosis
• hallmarks are peritoneal implants, adhesions or
  endometriomas

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AFS-R Classification

• Stage I (Minimal) 1- 5
• Stage II (Mild) 6-15
• Stage III (Moderate) 16-40
• Stage IV (Severe) gt40

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Indications for laparoscopy
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Number of pregnancies

• Within one year after completion of treatment 5
  (31)

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Statistical analysis

• Mann-Whitney test
• Students t-test
• Wilcoxon matched-pairs signed ranks test
• Paired t-test
• ?2-test

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Mode of action of GnRH-a

• continued administration results in
  desensitization of GnRH receptors of the
  pituitary
• initial stimulation of the pituitary-ovarian axis
• followed by suppression of gonadotrophin
  secretion and hypooestrogenism

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Benefits GnRH agonist

• shrinking fibroids before surgery
• management of endometriosis, ovarian
  hyperandrogenism, premenstrual syndrome,
  precocious puberty and dysfunctional uterine
  bleeding

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GnRH-a plus placebo

• hot flushes
• vaginal dryness
• loss of libido
• headache
• increased bone turnover leading to a decrease in
  BMD

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HRT rationale

• Oestrogen threshold hypothesis
• low E2 levels regression of oestrogen sensitive
  tissues (e.g. endometriosis)
• adding E2 increases E2 levels to maintain
  integrity of bone, relief of vasomotor symptoms
  and remaining of regression of endometriosis

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Lumbar vertebrae

• trabecular bone for more than 70
• susceptible of hypooestrogenism
• appendicular skeleton of the limbs are less
  oestrogenic sensitive

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Relevance BMD measurements

• small declines in BMD can increase actual
  fracture risk
• complete reversal of lumbar bone mineral density
  after 2 years following a six month GnRH-a
  treatment without add-back (Paoletti et al, 1996)
• BMD does not measure the microstructure of bone

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Prospective randomized placebo controlled trials
with follow-up laparoscopy