Editor’s Note: From time to time, research goes beyond collecting data and information to inspire hope for the future. The review article summarized by Laura Sullivan while on the FACTS online elective has this effect. Authors Check and Choe published a review of research in Gynecology & Reproductive Health to address the possibility of natural conception for women with declining ovarian reserve. [1] In her summary, Sullivan highlights the value of charting the female cycle, which can lead to earlier diagnosis of ovulatory dysfunction in women with premature ovarian failure, potentially increasing the likelihood of natural conception. To learn more about premature ovarian failure, join us in Pittsburgh, PA on March 21-22 for the 2025 FACTS Conference, where Dr. Naomi Whittaker, a NaPro Ob-Gyn physician and FACTS Advisory Council member, will address this important topic. The early bird deadline is THIS Saturday, February https://www.factsaboutfertility.org/2025-conference/1st, so register today!
Introduction
In 2022, Jerome Check and Jung Choe published a review titled, “Maximizing Correction of Infertility with Moderate to Marked Diminished Egg Reserve in Natural Cycles by Up-Regulating Follicle Stimulating Hormone Receptors.” The article discusses the role of follicle-stimulating hormone (FSH) and anti-Müllerian hormone (AMH) in determining ovarian reserve, emphasizing their significance in women with diminished ovarian reserve (DOR). Women with DOR typically present with elevated FSH levels and reduced levels of AMH.
FSH stimulates development of the ovarian follicle. If the follicles struggle to mature, the pituitary gland compensates by secreting higher levels of FSH. In turn, the developing follicles produce AMH, which serves as a marker of follicular reserve. Low levels of AMH indicate smaller cohorts of follicles, potentially insufficient for successful ovulation.
In women whose FSH levels remain chronically elevated, FSH receptors on granulosa cells become down-regulated via receptor internalization. This desensitizes the granulosa cells’ response to FSH, creating a state of FSH resistance and diminishing the likelihood of follicles reaching maturation and ovulation.
“In women whose FSH levels remain chronically elevated, FSH receptors on granulosa cells become down-regulated … creating a state of FSH resistance.”
In addition to hampering follicle maturation, FSH resistance is hypothesized to impair implantation of the embryo. Check and Choe referenced a 2005 study from the Medical College of Cornell University that found women with FSH levels ≥18 mIU/mL on day 3 of their cycle were unable to achieve a successful pregnancy following in vitro fertilization-embryo transfer (IVF-ET) despite receiving healthy-appearing embryos. [2] This led to the hypothesis that FSH receptors play a crucial role not only in ovulation but also in the production of unknown enzymes or proteins necessary for successful embryo implantation. Chronically elevated FSH levels may down-regulate the receptors that trigger synthesis of these hypothesized proteins, hindering implantation.
“In addition to hampering follicle maturation, FSH resistance is hypothesized to impair implantation of the embryo.”
A Productive Pilot Study
Based on this background knowledge, a pilot study was conducted to explore whether reducing FSH levels in women with premature ovarian failure (POF) could enhance FSH receptor sensitivity to restore ovulation and enable pregnancy. This decrease in FSH was accomplished by administering estrogen (E2) and human menopausal gonadotropin (hMG) to provide negative feedback on the anterior pituitary. If a mature follicle was identified, 10,000 IU of human chorionic gonadotropin (hCG) was given to induce ovulation. Five women with POF were recruited, all of whom had FSH levels ranging from 52 to 120 mIU/mL and had been amenorrheic for at least six months. After treatment with exogenous estrogen, four of the five women were able to ovulate, and three were eventually able to conceive naturally.
Results of Subsequent Study
Building on these findings, the researchers refined their methodology in a subsequent study. This new study featured 100 women who had been amenorrheic for at least a year, indicating apparent menopause. Rather than E2, they administered ethinyl estradiol (EE) to differentiate between exogenous estrogen given to patients and endogenous estrogen produced by their developing follicles. Whereas the pilot study used E2 and hMG, only EE was given in the subsequent study to suppress FSH.
If study participants failed to produce sufficiently rising E2 due to too much FSH suppression, a low dose of 75 IU of FSH was given. This selective use of gonadotropins was a more cost-effective approach. The participants’ progesterone levels were supplemented during their luteal phase.
While the live-birth rate observed in this study is lower than what may be achieved using IVF plus FSH sensitization, it is significant, as this was the first study to use this technique to enable women with amenorrhea to conceive naturally with their own eggs. The implications are profound, as women once deemed to have infertility now have renewed hope of conceiving naturally.
The authors found that for women who were eventually able to conceive, the average time from their initial diagnosis of POF was 2.2 years. For those who were unable to conceive, the average time from their initial diagnosis was 4.8 years. This provides evidence that although there is still hope for women with POF to conceive naturally, time is of the essence to optimize the success of this treatment protocol.
Earlier Diagnosis by Charting the Female Cycle
The FACTS Part B elective—Fertility Awareness for Women’s Health—emphasizes how a comprehensive understanding of the female cycle may reveal valuable insights into a woman’s overall health. By tracking cervical mucus, basal body temperature, and urinary hormone levels, women and their physicians can determine whether ovulation has occurred, assess the adequacy of the luteal phase to support early pregnancy, and identify whether bleeding patterns suggest optimal gynecologic health.
If more women are equipped with the knowledge and tools to chart their cycles effectively, and if their physicians and other medical professionals become proficient in interpreting these charts, ovulatory dysfunctions may be detected more quickly. This would facilitate earlier diagnosis in women experiencing POF, potentially identifying them before menstruation ceases entirely. With early detection, women have the opportunity to consider their fertility goals while interventions such as FSH sensitization remain a source of hope. Given the extensive health information provided by charting the female cycle, it is essential that both women and their healthcare professionals receive proper education on documenting and interpreting cycle charts.
“If more women are equipped with the knowledge and tools to chart their cycles effectively … ovulatory dysfunction may be detected more quickly… and women (would) have the opportunity to consider their fertility goals while interventions such as FSH sensitization remain a source of hope.”