Ovarian stimulation for fertility preservation in an oncology patient with etonogestrel implant in place

Abstract

Purpose

To describe a case of a young woman who presented for fertility preservation and underwent ovarian stimulation with an etonogestrel implant in place.

Methods

A 24-year old, gravida 0, with an etonogestrel implant and newly diagnosed lower extremity sarcoma and DVT desiring oocyte cryopreservation prior to adjuvant chemotherapy and radiation. To avoid delay in her oncologic care and allow for continued use of contraception post-retrieval, the patient underwent controlled ovarian hyperstimulation (COH) without removal of the etonogestrel implant.

Results

Baseline labs included follicle-stimulating hormone 9 mIU/mL, luteinizing hormone 4.9 mIU/mL, estradiol 42 pg/mL, anti-Müllerian hormone 5.1 ng/mL, and antral follicle count greater than 40. The patient was placed on an antagonist protocol and stimulated with 125 IU Gonal-F and 75 IU Menopur. She received a total of 12 days of gonadotropin stimulation. On the day of trigger, her estradiol was 1472 pg/mL, lead follicle 21.5 mm with a total of 25 follicles measured > 12 mm. She was triggered with 5000 U hCG. She had a total of 23 oocytes retrieved, 17 of which were metaphase II and vitrified.

Conclusions

COH and successful oocyte cryopreservation can be achieved in patients with an etonogestrel implant in situ without apparent detrimental effects to oocyte yield or maturity. Due to the etonogestrel implant’s inhibitory effects on LH, it is recommended to use an hCG trigger for final oocyte maturation.

Introduction

Fertility preservation counseling is standard of care in reproductive aged women diagnosed with malignancies requiring gonadotoxic therapy, as these treatments can often result in patients becoming infertile [1, 2]. Oocyte cryopreservation is an effective way to preserve female fertility [3] and is often performed expeditiously after a new cancer diagnosis due to the urgent need to start chemotherapy or radiation. Effective contraception is recommended while undergoing chemotherapy and immediately after treatment [4] due to the increased obstetric and fetal complications observed in patients receiving chemotherapy during pregnancy [5].

Long acting reversible contraceptives (LARCs), including intra-uterine devices and the etonogestrel implant, are highly effective forms of contraception and are becoming increasingly popular among reproductive aged women with a prevalence of 11.6% among US females using contraception [6, 7]. LARCs are expensive [8] and require invasive procedures for both placement and removal. An immediate initiation of ovarian stimulation for fertility preservation without LARC removal is time and cost effective. Controlled ovarian hyperstimulation (COH) in patients with levonorgestrel-releasing intrauterine devices (LNG-IUD) has been well documented and has shown minimal effects on cycle performance [9, 10]. However, there have been no documented reports of patients undergoing COH with the etonogestrel implant.

We herein present a report of a young woman with recently diagnosed high-grade sarcoma of the left knee planning for adjuvant chemotherapy and radiation who was referred to our clinic for fertility preservation with an etonogestrel implant in place. To the best of our knowledge, this is the first reported case of successful COH and oocyte cryopreservation in a patient with an etonogestrel implant in situ.

Materials and methods

Institutional Review Board exemption was approved for the submission of the following case report. The patient was a 24-year old, gravida 0 with previously unremarkable medical history and limited surgical history that consisted of ankle fracture repair. Her contraceptive history included use of oral contraceptive pills for 3 years followed by etonogestrel implant currently in place for 2 years. She initially presented with a mass in the popliteal region of her left knee and underwent imaging followed by biopsy that returned as a sarcoma. She subsequently underwent a wide local excision with pathology returning CIC-DUX4 round cell sarcoma. The plan made by her oncology team was for adjuvant chemotherapy and radiation as soon as possible. She was referred to our clinic for fertility preservation before undergoing these treatments. Additionally, 5 days prior to evaluation in our clinic, she was diagnosed with a left lower extremity DVT and started on apixaban 10 mg daily.

On initial consultation, the patient reported having an etonogestrel implant placed 28 months prior, and therefore was not due for removal/exchange for an additional 8 months. Her menstrual cycles were irregular since placement of the implant, and her last menstrual period was unknown. Prior to etonogestrel implant placement, the patient was on oral contraceptive pills for 3 years for menstrual cycle regulation without complications. Ovarian reserve testing was completed at the initial consultation. Due to the plan to initiate chemotherapy and radiation as soon as possible, the need for contraception during these treatments, and no known detrimental effects of etonogestrel on COH, the plan was made to proceed with COH and oocyte cryopreservation without removing the etonogestrel implant. Coordinating care with her oncologist, she started COH 2 days after initial consultation with an antagonist protocol. Anti-coagulation was also coordinated with her hematologist and oncologist, with the decision to discontinue the apixaban 72 h prior to oocyte retrieval and resume 12 h after.

Results

Random ovarian reserve testing at the time of initial consultation revealed follicle-stimulating hormone of 9 mIU/mL, luteinizing hormone of 4.9 mIU/mL, estradiol of 42 pg/mL, anti-Müllerian hormone of 5.1 ng/mL, and quiescent ovaries with antral follicle count greater than 40. The patient was started on an antagonist protocol with initial gonadotropin dosage of 125 IU Gonal-F and 75 IU Menopur. Her stimulation protocol, laboratory values, and follicular response are listed in Table 1. To summarize, she received a total of 12 days of gonadotropin stimulation. On the day of trigger, estradiol was 1472 pg/mL, and the lead follicle was 21.5 mm with a total of 25 follicles measured > 12 mm. She was triggered with 5000 U hCG. She had a total 23 oocytes retrieved, 17 of which were metaphase II and vitrified (three metaphase I, one germinal vesicle, and two atretic oocytes were discarded).

Table 1.

Ovarian stimulation chart

Stimulation day
	1	2	3	4	5	6	7	8	9	10	11	12/day of hcg trigger
Gonal–F, IU	125	125	125	175	175	175	175	175	175	175	175
Menopur, IU	75	75	75	75	75	75	150	225	225	225	225
Ganirelex, mg							0.25	0.25	0.25	0.25	0.25	0.25
E2, pg/mL				88		364		568			1294	1472
Progesterone, ng/mL						0.7						2.1
Lead follicle, mm				10.5		12		15.5			20.5	21.5
Follicles ≥ 10 mm				1		5		14			22	25

On post-operative day 1, she presented to the emergency department (ED) with complaints of abdominal pain, nausea, and emesis. Laboratory workup was unremarkable and pelvic ultrasound was consistent with recent ovarian stimulation with small hemoperitoneum. She was expectantly managed with oral pain medication and anti-emetics and discharged home.

Discussion

To the best of our knowledge, this is the first case report of a patient undergoing COH with an etonogestrel implant in situ. Overall, the patient had favorable ovarian reserve testing, without any evidence for initial pituitary or ovarian suppression. Etonogestrel acts by binding progestin receptors located along hypothalamic-pituitary-ovarian-genital tract axis to interfere with ovulation, fertilization, and implantation. Its main mechanism is through the prevention of ovulation by inhibiting the LH surge [11]. This effect differs from that of long-term oral contraceptive use, which often results in significant pituitary and ovarian suppression that can be detrimental to ovarian stimulation outcomes and may increase length of stimulation [12]. Given the inhibitory effects of etonogestrel on LH release, a decision was made to start stimulation with administration of both exogenous FSH and LH. Further, we did not expect a robust LH surge to be possible from a GnRH agonist trigger; thus, HCG only trigger was utilized. The patient had an excellent follicular response to exogenous gonadotropin stimulation with 23 oocytes retrieved (17 of which were metaphase II) and did not require an extended stimulation time frame. Given this patient’s favorable results, it is reasonable to avoid removing an etonogestrel implant in oncofertility patients undergoing COH.

Of note, the serum E₂ levels did not correlate as expected with the robust follicular response, and the lower E₂ levels were not indicative of poor oocyte yield or maturity. These findings are similar to what is seen in patients that undergo COH with LNG-IUD [9, 10]. This suggests that E₂ may not be a good marker for follicular maturity or ovarian stimulation response and should not be solely relied upon when making clinical decisions regarding dosage alterations or trigger timing. The exact mechanism for why LNG-IUD or etonogestrel implant patients have lower E₂ levels compared with controls merits further consideration, but it did not appear to have any effects on follicular growth, oocyte yield, or maturity. It is possible that the inhibitory nature of the etonogestrel implant on LH release results in decreased theca cell stimulation therefore causing reduced aromatization of androgens to estrogens leading to diminished elevation in estradiol. However, in patients undergoing IVF with hypothalamic hypogonadism, supplementation with human Menopur gonadotropin (HMG) mimics typical follicle growth and estradiol rise [13]. Thus, progestin inhibition of LH release alone does not explain the suppressed estradiol rise in these patients.

Additionally, there are no reports of patients undergoing COH and oocyte retrieval while on apixaban. Apixaban is a direct factor Xa inhibitor with a half-life of approximately 12 h. It is an oral anti-coagulant, and due to its ease of use and lack of lab monitoring requirement, it is becoming increasingly utilized among patients requiring anticoagulation. Perioperative management recommendations suggest that apixaban should be held for 24–72 h prior to procedures and resumed 24–72 h post-procedure with time depending on the bleeding risk of the procedure [14]. In our case, the decision by hematology was to hold apixaban for 72 h prior to the procedure due to the high risk of ovarian bleeding at the time of oocyte retrieval, and resume 12 h post-procedure due to the high-risk stratification of the patient with a recently diagnosed active DVT, malignancy, and elevated estradiol levels. While she did present to the ED on post-operative day 1, her work up returned consistent with mild hemoperitoneum and symptoms resolved with oral pain medication and oral anti-emetics, and her remaining post-operative course was uncomplicated.

While COH was successful in this patient, it cannot be presumed that her stimulation would have been more or less effective without the etonogestrel implant in place. She had an AMH of 5.1, indicative of an anticipated robust stimulation, and her eventual oocyte yield in the setting of this AMH and an antagonist cycle is similar to previously published correlations [15]. Approximately 74% of the retrieved oocytes were mature, which is in line with the average rate of 70–80% maturity for retrieved oocytes [16]. Further, while COH was effective, data on fertilization and pregnancy rates remain unknown and will require future study.

Conclusions

Controlled ovarian hyperstimulation and successful oocyte cryopreservation can be achieved in a patient with an etonogestrel implant without apparent detrimental effects to oocyte yield or maturity. Initiating stimulation with both exogenous FSH and LH should be considered, along with the use of HCG only trigger. Estradiol levels may not correlate with the follicular response or oocyte maturity and should not be solely relied upon when making clinical decisions regarding gonadotropin dosing or triggering.

Authors’ contributions

All authors contributed to the manuscript according to the submission guidelines.

Data availability

All data and materials are included in the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Code availability

Not applicable.