Study of a Progestin to Prevent Bleeding Associated With Initiation of Medical Menopause With GnRH Agonist

Gonadotrophin releasing hormone is a decapeptide produced in the hypothalamus that
stimulates both follicle stimulating hormone and lutenizing hormone secretion from the
anterior pituitary in response to a number of endocrine feedback loops that include
estradiol, progesterone, and inhibin. Leuprolide acetate is a synthetic decapeptide and a
potent gonadrotropin-releasing hormone agonist that can be used in a number of clinical
conditions such as endometriosis, chronic pelvic pain, uterine leiomyomas, adenomyosis,
central precocious puberty and in-vitro fertilization.

This agonist is more potent that the natural gonadotrophin releasing hormone peptide as it
has a stronger affinity for the receptor and also has a longer half-life. Following
administration the high levels of gonadrotropin-releasing hormone agonist produce an
immediate increase in pituitary luteinizing hormone and follicle stimulating hormone
secretion ('flare-up'), which leads to an increase in serum estradiol within 2 days of
administration However, unlike the physiological state, where gonadotrophin releasing
hormone is produced in a pulsatile fashion, the tonically elevated levels of
gonadrotropin-releasing hormone agonist will cause a downregulation of pituitary receptors
and desensitization of the pituitary gonadotrophs which leads to a hypogonadotropic state by
the fourth week post injection. This suppression is the basis for the clinical application
of this drug in gynecology. With the initial 'flare-up', however, there can be an episode of
uterovaginal bleeding secondary to the endometrial impact of the temporary, self limited,
high circulating levels of estradiol. that appear to in the second week. This bleeding can
especially be a cause for concern in women who are already anemic at baseline.

A suggested approach for reducing or preventing this flare-related bleeding is the
administration of a progestin or estrogen-progestin combination preparation in conjunction
with the initiation of gonadrotropin-releasing hormone agonist therapy. The putative role
of the progestin is to reduce the responsiveness of the endometrium to estradiol by
downregulating endometrial estrogen receptors. Such an approach could mitigate the impact of
the estradiol flare thereby reducing the volume of the flare-related bleeding, or,
potentially, eliminate it altogether. However, a systematic review of published literature
fails to identify any studies evaluating methods designed to reduce bleeding associated with
the gonadrotropin-releasing hormone flare. The databases searched included the Cochrane
Database of Systematic Reviews as well MEDLINE using the PubMed search engine. Search words
and phrases included: gonadrotropin-releasing hormone agonist, bleeding,
gonadrotropin-releasing hormone agonist flare progestin, and leuprolide acetate. The current
instructions for use from the FDA for approved gonadrotropin-releasing hormone agonist
compounds such as leuprolide acetate do not recommend or mandate the use of progestins with
the use of gonadrotropin-releasing hormone agonist. The standard of care at this time,
therefore, is that progestins or estrogen-progestin compounds are not used when initiating
gonadrotropin-releasing hormone agonist therapy. As a result it seems appropriate to perform
structured investigation of the role of progestin-based regimens for the mitigation of
gonadrotropin-releasing hormone agonist-induced flare bleeding.

The proposed project is a pilot randomized trial to be performed in selected
gonadrotropin-releasing hormone agonist-naieve women who are initiating
gonadrotropin-releasing hormone agonist therapy with leuprolide acetate 11.25 mg as
determined by their clinicians. The study group will be randomized into one of two arms:
Those receiving medroxyprogesterone acetate administered orally in a dose of 20 mg twice
daily for the first three weeks after their first leuprolide acetate injection and the
"control" group, who receive no progestin therapy. Medroxyprogesterone acetate was selected
because it is FDA-approved for abnormal uterine bleeding, it is in widespread use and is
well tolerated, and there are multiple studies describing the use of dosages higher than
those proposed for this study. One such study was performed and published by our group
evaluating daily doses of medroxyprogesterone acetate as high as 60 mg for the treatment of
acute uterine bleeding in nongravid patients. If the investigators are able to demonstrate
that the use of medroxyprogesterone acetate significantly reduces or eliminates the volume
of uterine bleeding associated with the initiation of gonadrotropin-releasing hormone
agonist therapy, women in the KP system and elsewhere may be spared this side effect of
treatment. Such a finding may have special value for women who are already anemic and,
consequently, unable to tolerate a treatment associated bleed.

Inclusion Criteria:

1. Premenopausal women 18-50 years of age

2. Requiring gonadrotropin-releasing hormone agonist for any indication except ovulation
induction

3. If there is abnormal uterine bleeding, such bleeding is not obviously related to
structural defects such as polyps or submucous leiomyomas; subserosal and intramural
myomas (International Federation of Gynecology and Obstetrics Classification 3-8
inclusive) are acceptable

Exclusion Criteria:

1. Currently pregnant

2. Recent used of gonadrotropin-releasing hormone agonist

1. 1 month depot formulation eg leuprolide acetate 3.75, within 90 days

2. 3 month depot formulation eg leuprolide acetate 11.25 within 180 days

3. Currently has an intrauterine contraceptive device

4. Currently on gonadal steroids (including birth control pills, rings, or implantable
or injectable agents)

5. History of breast cancer

6. Currently undergoing ovulation induction

7. History of adverse reactions to gonadal steroids

8. Hemoglobin <8 mg/dl as measured within 30 days of enrollment (Baseline hemoglobin is
standard of care for patients initiating gonadrotropin-releasing hormone agonist
therapy)

9. Weight above >250 lbs

10. Has a known submucous leiomyoma ( International Federation of Gynecology and
Obstetrics Class type 0, 1, 2)