Ovulation; Failure or Lack of Clinical Trial
Official title:
Can Hormonal Effects of the Oral Gonadotropin Releasing Hormone (GnRH) Antagonist Withstand When Administered at Different Points in the Menstrual Cycle?
The purpose of this study is twofold: First, to see if elagolix can suppress gonadotropin and ovarian hormones in the short-term period, when only administered for a 72-hour period. If elagolix effectively suppresses gonadotropin and ovarian hormones in a timely manner, it could be used to alter aspects of the menstrual cycle, depending on when administered. Second, is there a window for when elagolix functions best? While other studies initiate elagolix at the start of a woman's menstrual cycle, investigators of this study want to determine if administering elagolix at various points in a woman's menstrual cycle alters its ability to suppress gonadal and ovarian hormones.
Gonadotropin-releasing hormone (GnRH) and its analogs have been utilized in clinical medicine
since the early 1970s. The GnRH analog is more potent with a longer half-life than native
GnRH. When administered continuously rather than in a more physiologic pulsatile manner, the
initial stimulation of pituitary gonadotrophs is followed by pituitary desensitization1,2.
This ultimately leads to inhibition of the pituitary-gonadal axis. This downregulation
facilitates the use of GnRH agonists for the treatment of various medical conditions,
including precocious puberty, endometriosis, uterine leiomyomata, prostate cancer, and
assisted reproductive technology (ART)1,2.
Like GnRH agonists, antagonists of GnRH have proven to efficiently suppress pituitary and
ovarian hormone production. However, unlike the agonist, the GnRH-antagonist competitively
binds to the GnRH-receptor1,2. The antagonist bypasses the initial flare effect and does not
require the initial period of administration for pituitary desensitization of GnRH receptors.
As a result, there is rapid prevention of gonadotropin secretion and antagonist effect on the
ovary1-4.
In addition to the enhanced efficiency of using a GnRH-antagonist, it has shown to be more
tolerable with fewer side effects when compared to the older GnRH agonist1-5. Particularly in
ART, GnRH agonists are associated with hot flashes, ovarian cyst formation, and ovarian
hyperstimulation syndrome (OHSS)6. Conversely, GnRH antagonists have been shown to
significantly reduce the incidence of OHSS, and are not associated with cyst development or
hot flashes6. It is important to note that in ART literature, administration of a
GnRH-antagonist has been via a subcutaneous injection, formulated as ganirelix, detirelix or
cetrotide3-5.
Fluker et al investigated the impact of the subcutaneous GnRH-antagonist on gonadotropin and
ovarian hormone production when administered at different points of the menstrual cycle:
mid-follicular phase, preovulatory phase, and early luteal phase5. Investigators found that
the GnRH-antagonist successfully suppressed gonadotropin hormones irrespective of phase of
menstrual cycle. Suppression of ovarian hormones, and particularly suppression of the LH
surge, was evident only when the GnRH-antagonist administered in mid-follicular and early
luteal phases5.
In an effort to avoid a subcutaneous injection and ease patient administration, an oral
GnRH-antagonist has recently been developed: Elagolix. Research has shown that elagolix
similarly suppresses gonadotropin and ovarian hormones compared to its injectable formulary7.
Ng et al investigated the pharmacokinetics of elagolix over a 21-day period, while also
investigating elagolix's suppression of gonadotropic and ovarian hormones at varying doses
when administered during a natural menstrual cycle7. Time to maximum concentration of
elagolix was 1.0-1.5 hours, with a half-life of about 4-6 hours. While maximum suppression of
follicle stimulating hormone (FSH) and LH occurred in all doses administered, maximum
suppression was seen in the elagolix 300mg BID and 400mg BID groups. Rebound to baseline FSH
and LH was evident within 24-48 hours from last dose of elagolix. Maximum estradiol
suppression was seen when administered at 200mg BID or higher doses, and maximum progesterone
suppression was seen in all doses 100mg BID or higher. While elagolix was administered for a
21-day period, the greatest decrease in gonadotropin and ovarian hormone levels was seen in
the first three days of administration at any dose7.
Thus far, the Federal Drug Administration (FDA) has approved elagolix for the management of
moderate to severe pain associated with endometriosis. Approved regimens include one 150mg
tablet once daily or one 200mg tablet twice daily7-10. Like the injectable GnRH antagonist,
the oral GnRH antagonist efficiently manages pain symptoms in endometriosis via suppression
of estrogen secretion. Estrogen is thought to play a role in the pathophysiology of
endometriosis via its stimulatory effects on the endometrium and its stimulatory effects on a
woman's inflammatory milieu, both at the local and systemic level10.
While elagolix has been proven to effectively suppress gonadotropin and ovarian hormones,
like the injectable GnRH antagonists, elagolix has yet to be used in conditions other than
endometriosis, such as in cases of ART7. More specifically, the impact of elagolix in the
short-term period for cases of COH has yet to be studied.
Subjectively looking at Ng et al's data, there are sharp declines in FSH, LH, estradiol, and
progesterone within the first three days of administering elagolix, and these concentrations
continue to decline, but at a less steep slope, from days 4 through day 21 of
administration7. It appears that the first three days are crucial to hormonal suppression7.
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| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT04942457 -
Feasibility and Safety of Fasting in Fertility Treatment
|
N/A |