Hormonal Effects of the Oral Gonadotropin Releasing Hormone (GnRH) Antagonist at Different Periods of the Menstrual Cycle

August 14, 2019 updated by: Frank Stanczyk, University of Southern California

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Anticipated)

12

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 39 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Healthy volunteers from USC Fertility
  • Documented ovulation with a serum mid-luteal progesterone ≥3pg/mL
  • Ovulatory with a 24-35-day cycle
  • Ages 18-39
  • Body Mass Index (BMI) 18.1-30.0kg/m2
  • Consistent condom use for contraception
  • Not desiring or seeking pregnancy

Exclusion Criteria:

  • Allergy to injectable or oral GnRH-antagonist
  • FSH ≥ 10 IU/L or LH ≥ 10 IU/L in early follicular phase iii. Known liver disease iv. Known osteoporosis v. Pregnancy vi. Current use of drugs metabolized by the liver enzyme CYP3A, specifically ketoconazole, rifampin, digoxin, oral midazolam, or rosuvastatin.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Screening
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Early Follicular Phase
Women enrolled will be anywhere from cycle day 1 through 5 of their menstrual cycle and take elagolix 200mg oral tablet BID for 3 days total.
Drug: Elagolix 200 MG Oral Tablet [Orilissa]
oral tablet given twice daily
Active Comparator: Late Follicular Phase
Women enrolled will be anywhere from cycle day 8 through 13 of their menstrual cycle and take elagolix 200mg oral tablet BID for 3 days total.
Drug: Elagolix 200 MG Oral Tablet [Orilissa]
oral tablet given twice daily
Active Comparator: Luteal Phase
Women enrolled will be anywhere from cycle day 21 through cycle day 26 of their menstrual cycle and take elagolix 200mg oral tablet BID for 3 days total.
Drug: Elagolix 200 MG Oral Tablet [Orilissa]
oral tablet given twice daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Suppression of gonadotropin and pituitary hormones as measured by hormonal assay status post short-term administration of elagolix
Time Frame: measured over 4 days
Measure serum concentrations of follicle stimulation hormone (FSH), luteinizing hormone (LH), estradiol, progesterone at baseline and throughout three-day course of elagolix
measured over 4 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time interval to next menses
Time Frame: up to 4 weeks
Calculate number of days from elagolix consumption to next menses
up to 4 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Southern California

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

October 1, 2019

Primary Completion (Anticipated)

October 30, 2020

Study Completion (Anticipated)

July 1, 2021

Study Registration Dates

First Submitted

August 7, 2019

First Submitted That Met QC Criteria

August 14, 2019

First Posted (Actual)

August 19, 2019

Study Record Updates

Last Update Posted (Actual)

August 19, 2019

Last Update Submitted That Met QC Criteria

August 14, 2019

Last Verified

August 1, 2019

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • APP-19-02687

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

IPD Plan Description

No, data will not be available to other researchers. At the study completion, all patient data will be destroyed in the HIPAA compliant manner.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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