Gonadotropin-releasing hormone agonist-induced ovarian hyperstimulation: low-dose side effects in women and monkeys.
OBJECTIVE
To determine whether low (subtherapeutic) doses of gonadotropin-releasing hormone agonists (GnRH-a) can cause ovarian hyperstimulation.


METHODS
The study is in two parts: a preliminary clinical trial of women and a follow-up study in laboratory primates.


METHODS
Normal human volunteers were studied in an academic research environment; primates were in a conventional laboratory setting.


METHODS
Human volunteers were selected on the basis of apparent normal health. The monkeys were believed to be of normal reproductive status.


METHODS
Gonadotropin-releasing hormone agonists were administered at subtherapeutic doses.


METHODS
After observing ovarian hyperstimulation in two of five women receiving low doses of GnRH-a, a study was specifically designed to test the hypothesis that at low (subtherapeutic) doses of GnRH-a the "flare-effect" can be sustained without achieving down regulation.


RESULTS
The data in women and monkeys suggest that a highly individualized response to low GnRH-a doses can be manifested as ovarian hyperstimulation.


CONCLUSIONS
Four points of interpretation are offered: (1) that subtherapeutic doses of GnRH-a can cause ovarian hyperstimulation and related sequelae; (2) this may be a unique observation in that, typically, lower doses of medications have a lower incidence of negative side effects; (3) the findings suggest that GnRH-a prescribed in self-administration regimens may be more prone to such problems in noncompliant patients; and (4) the hyperstimulation response of the ovaries to low GnRH-a doses may indicate a new approach to controlled ovulation induction, although wide individualism was found.
Navot
D
D
Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, Norfolk.
Rosenwaks
Z
Z
Anderson
F
F
Hodgen
G D
GD
D000281:Administration, Intranasal; D000328:Adult; D000818:Animals; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D004958:Estradiol / Q000097:blood; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D016729:Leuprolide; D008252:Macaca fascicularis; D008597:Menstrual Cycle / Q000187:drug effects; D017274:Nafarelin; D010053:Ovary / Q000187:drug effects / Q000502:physiology*; D010902:Pituitary Gland / Q000187:drug effects / Q000502:physiology*; D011374:Progesterone / Q000097:blood; D017329:Triptorelin Pamoate / Q000031:analogs & derivatives*
D003692:Delayed-Action Preparations; D017329:Triptorelin Pamoate; D017274:Nafarelin; D007987:Gonadotropin-Releasing Hormone; D011374:Progesterone; D004958:Estradiol; C019176:Tryptal; D016729:Leuprolide