By: Alexandra Northrup
Editor’s Note: During National Infertility Awareness Week, we are featuring a review article and pilot study by Jerome Check and Jung Choe published in 2022 in Gynecology & Reproductive Health. [1] The authors reviewed the existing literature regarding restoration of fertility in women with diminished ovarian reserve, premature ovarian failure, or in the perimenopause phase. Alexandra Northrup was in her fourth year of medical school when she summarized the article while on the popular FACTS elective in fertility awareness taught through Georgetown University School of Medicine.
Introduction
The review article and pilot study by Check and Choe [1] summarized below explores strategies that have been used to enhance fertility in women with a significantly diminished ovarian reserve (DOR). The authors suggest that up-regulation of follicle-stimulating hormone (FSH) receptors during a natural menstrual cycle may augment the ovarian response to hormonal stimulation, thus increasing the likelihood of ovulation and conception. They discuss methods to achieve such up-regulation of FSH receptors, such as central directed treatments to modulate FSH levels and the use of mild ovarian stimulation protocols. Most important is the emphasis on crafting an individualized treatment approach to optimize fertility outcomes in this patient population.
Hypothesis
The likelihood of ovulation and subsequent conception in a patient with DOR or premature ovarian failure may improve by restoring FSH receptors to the surface of granulosa-theca cells, thus increasing the sensitivity of remaining follicles to hormonal stimulation.
Understanding the Physiology
The need to restore an appropriate or adequate ovulation cycle is paramount for successful conception, maintenance, and success of a pregnancy. In women with DOR, there is often premature ovarian failure (in younger women) or entrance into the perimenopause or menopausal stage (in older women). A hallmark of both conditions is hormonal derangement and subsequent dysfunction of the hypothalamic-pituitary-gonadal (HPG) axis. In this case, it mimics a menopausal hormonal pattern of elevated FSH with decreased anti-Mullerian hormone (AMH), inhibin-B, and insulin-like growth factor-1 levels.
The hallmark of menopause is decreased ovarian function from age-related ovarian follicle loss, leading to decreased estrogen and progesterone levels, which results in the loss of negative feedback on the pituitary gland. This loss of negative feedback results in unregulated GnRH levels, leading to increased FSH and LH levels. In response to such chronic exposure to elevated FSH, the ovarian follicle cells down-regulate FSH receptors to prevent burnout from continuous FSH stimulation. Therein lies the problem in a patient with premature ovarian failure or diminished ovarian reserve: a decrease in FSH receptors as a protective mechanism becomes pathologic in the female reproductive cycle by inhibiting the appropriate growth and maturation of a follicle for ovulation.
“In a patient with premature ovarian failure or diminished ovarian reserve, a decrease in FSH receptors … inhibit(s) the appropriate growth and maturation of a follicle for ovulation.”
Methodology
The authors reviewed the existing literature in women with difficulty getting pregnant regarding successful re-establishment of fertility and even successful pregnancy through FSH receptor up-regulation. Upon review, they suggested hormonal modulation to re-establish the body’s physiologic HPG axis signaling and conducted a pilot study.
To restore down-regulated FSH levels in the granulosa-theca cells, patients received pharmacologic estrogen (ethinyl estradiol) followed by human menopausal gonadotropin (hMG). Alongside this regimen, ultrasonography was performed to confirm the formation of a mature follicle (average diameter >18mm) followed by successful ovulation. At that point, human chorionic gonadotropin (hCG) was given to maintain the corpus luteum with the goal of assisting implantation of the fertilized egg.
“To restore down-regulated FSH levels in the granulosa-theca cells, patients received pharmacologic estrogen (ethinyl estradiol) followed by human menopausal gonadotropin (hMG).”
The pilot study comprised five cases of women with >6 months of amenorrhea and marked estrogen deficiency (E2 < 20pg/mL) with increased FSH levels (>50 mIU/mL), indicating diminished ovarian reserve, premature ovarian failure, or perimenopausal status. The participants were treated with 2.5-5mg/day of conjugated estrogen until FSH was found to decrease to <11mIU/mL. At this point, hMG was given to initiate the formation of a mature follicle, tracking ovulation during each treatment cycle using ultrasound.
Results
Check and Choe referenced a number of case reports on women with DOR, premature ovarian failure, hypergonadotropic hypogonadism, and studies on ovulation induction for purposes of fertility and conducted their own pilot study using the parameters described above. Although all patients had successful ovulation at some point during treatment, some did not achieve ovulation on cycle 1 of treatment. There was variable success with conception in these patients.
“Although all patients had successful ovulation at some point during treatment … there was variable success with conception in these patients.”
The authors also evaluated ways to optimize a woman’s overall health prior to attempting to conceive. This included considering the presence of pelvic pain disorders due to ectopic endometrial implants, hypothesized to be caused by increased inflammatory cells within the pelvic tissues. A marker, BCL6, was discovered in the endometrial biopsies of women with endometriosis, and it is thought to indicate the inflammatory load a patient experiences. Minimizing such inflammation was thought to improve outcomes in this population.
A final evaluation involved cases of dextroamphetamine sulfate supplementation to improve fecundity. The review suggested the increased release of dopamine from the sympathetic nervous system decreased inflammation and subsequent permeability of pelvic tissues, while allowing the normal inflammatory process needed to establish spiral arteries as the placenta develops.
Discussion
This study evaluated the literature that exists regarding restoration of fertility in women with DOR, premature ovarian failure, and even those in perimenopause. For patients wishing to conceive, this research is groundbreaking in the way it can restore fertility physiologically, and avoid some of the physical, emotional, medical, and financial burdens of other forms of artificial reproductive technologies (ART).
A limitation of this review is the significant cost of hormone replacement medications to re-establish appropriate FSH receptor levels and responsiveness. According to this review, the medications required include ethinyl estradiol, progesterone vaginal suppositories to maintain an appropriate luteal phase, GnRH antagonists (if unable to receive estrogen supplementation), hMG, and hCG.
With respect to this science being used in medical practice, it would be important to design a randomized controlled trial to evaluate the efficacy of these methods compared to other methods to restore fertility. Specifically, it would be important to look at time-to-conception, ability to maintain the pregnancy, outcomes of the pregnancy/delivery, financial, time and emotional burden ratings, and attitudes among medical professionals toward this intricate and nuanced science.
Strengths of this review lie in its thorough evaluation of the literature, strong foundation on physiology and endocrinology, and its emphasis on a holistic, individualized approach for each patient treated.
References
[1] Check JH, Choe JK. Maximizing Correction of Infertility with Moderate to Marked Diminished Egg Reserve in Natural Cycles by Up-Regulating Follicle Stimulating Hormone Receptors. Gynecol Reprod Health. 2022; 6(4): 1-7.
ABOUT THE AUTHOR
Allie Northrup
Allie Northrup is a fourth-year medical student at Liberty University in Lynchburg, VA. She completed her undergraduate education at Marist College in Poughkeepsie, NY. She plans to pursue residency in obstetrics and gynecology and is interested in health equity, caring for the underserved, and empowering a woman’s autonomy in healthcare. She enrolled in the FACTS elective to learn more about fertility awareness-based methods and add these methods to her contraception/fertility repertoire.
Inspired by what you read?
You can support the ongoing work of FACTS here. To connect with a member of our team, please email development@factsaboutfertility.org. Interested in becoming an individual or organizational member? You can learn more and register here. To discuss with a member of our team, please email membership@factsaboutfertility.org.
