SIRM has a local clinic close to my office. I just finished treating a client who completed a cycle with SIRM, with great success! She was refused by 2 other fertility clinics due to her long and complicated history. I think for some women SIRM offers interesting protocols and strategies for couples with usual cases. SIRM published a journal article about one of their protocols. I find the theory behind it to be a solid solution for “poor responders”. My client, the “poor responder”, did not have a poor response with her IVF cycle and had 10 follicles retrieved with 3 for transfer.
I worked with my client for 4 months before her IVF cycle with herbs and acupuncture. One aspect I worked on was the lowering of androgens and eliminating cysts. As mentioned in my previous article, androgens are like dampness and cause follicle quality to be poor. Another part of my client’s treatment was nourishing yin. Yin is similar to estrogen and is important to help with follicle quality. Yin bathes the follicles in nutrients, which promotes smooth growth and avoids premature development. Strong yin provides a base to allow the ovaries to function at optimum and can decrease (in some cases) the over production of androgens. The over secretion of LH leading to increased androgen production can be caused by heat in the blood from a lack of yin. By addressing this imbalance, the ovary will start to receive correct messages for follicular development. By eliminating suffocating dampness and nourish yin, my client found the amount of cysts decreased, FSH dropped and ovulatory pain disappeared. In some facets, Chinese medicine mirrored her SIRM protocol and possibly laid the foundation for her successful IVF cycle and pregnancy.
Gonadotropin-releasing hormone agonist/antagonist conversion with estrogen priming in low responders with prior in vitro fertilization failure
Jeffrey D. Fisch, M.D., SIRM
Fertility and Sterility, Feb 2008 issue
Because most genetic errors occur at ovulation, manipulation of the hormonal environment surrounding the oocyte before ovulation may increase the chance of that oocyte completing meiosis normally. Primary follicles are metabolically inactive, and follicular growth occurs in waves. Because the outcome of meiosis is not determined until fertilization, if even some of these inactive follicles can be presumed genetically normal, then women with a history of aneuploid eggs could potentially still produce genetically normal ones in a subsequent cycle.
The most prevalent approaches for treating poor-prognosis patients at present are the short protocol, also known as the microdose gonadotropin-releasing hormone (GnRH) agonist “flare” and the GnRH antagonist protocol. Neither of these protocols has been especially effective in improving ART outcomes in these patients. The initial flare of follicle-stimulating hormone (FSH) in the short protocol may be promoting follicular development, but the luteinizing hormone (LH) flare that occurs with it may be simultaneously promoting apoptosis. In a similar fashion, the standard antagonist protocol exposes the maturing oocytes to the patient’s own endogenous androgen production during the 6 to 7 days of stimulation before development of a mature follicle. Even low levels of androgen could be significant in patients who are overly sensitive.
Using a hypothesis of androgen oversensitivity (as opposed to the androgen overproduction commonly seen in association with anovulation), we developed a protocol promoting estrogen dominance in the ovary. Using GnRH agonist/antagonist conversion with estrogen priming, we have been able to achieve success in women failing the short protocol or the standard GnRH antagonist approach.
All patients were pretreated with estrogen/progestin oral contraceptive pills for 1 to 3 weeks. The GnRH agonist (Lupron) was started in a standard long protocol, overlapping the last 5 to 7 days of oral contraceptive. The GnRH agonist was stopped with the onset of menses and replaced by low-dose GnRH antagonist on cycle day 2.
Estradiol valerate, was given intramuscularly every 3 days for two doses. Estrogen suppositories were used to maintain the endometrium until at least one follicle measured 15 mm. Follicular development was then stimulated using recombinant FSH. After the first 2 days, hMG at was substituted for the recombinant FSH. The average patient needed 13 days of stimulation before hCG administration. No cases of overstimulation occurred. Ovulation was triggered using hCG when at least one follicle was 18 mm and half of the remainder were 15 mm.
In this cohort of 137 low responders with prior IVF failure aged 38 to 42 years, there were a total of 37 ongoing gestations (27%). By diagnosis, ongoing gestations were achieved in 35% (14 out of 40) of women with elevated FSH levels, 29% (15 out of 52) of women with unexplained poor response, 19% (5 out of 26) of women with advanced maternal age, 17% (2 out of 12) of women with severe endometriosis, and 14% (1 out of 7) of women with decreased ovarian reserve.
When stratified by age, women <38 produced significantly more metaphase II oocytes and fertilized embryos (6.9 and 5.4, respectively) than women 38 to 42 (5.3 and 4.1; P<.05).
Developmental events in the follicle culminating in oocyte reactivation are hormonally controlled by endocrine, paracrine, and autocrine factors. In a natural ovulatory cycle, the dominant follicle is the one most capable of creating an estrogenic microenvironment surrounding the oocyte. Ovarian theca cells can produce androgens, but only granulosa cells catalyze these androgens into estrogen. Aromatase activity is increased by FSH and decreased by LH. Also, FSH and estradiol promote accumulation of granulosa cell–FSH receptors. Although FSH alone promotes initial follicular development, the final stages of maturation are optimized by LH. Oocytes in an estrogenic microenvironment mature and ovulate, whereas oocytes in an androgenic microenvironment undergo apoptosis. Androgen dominance in the early follicular phase promotes apoptosis.
Male hormone exposure in the early proliferative phase is detrimental to oocyte quality. In an androgenic environment, preantral follicles favor conversion to 5-α reduced androgens rather than to estrogen. These androgens cannot be further converted to estrogen, and they inhibit aromatase activity. Exposure to LH is also reported to down-regulate the formation of gap junctions between granulosa cells and close existing channels necessary for coordinated follicular growth.
Pretreatment with estrogen/progestin oral contraceptive pill is important to establishing an estrogenic environment. The dual actions of progestin-mediated LH suppression and estrogen saturation result in decreased follicular androgen levels. Over suppression from the pill has been a potential concern, but because its actions are central, direct ovarian stimulation with exogenous FSH should overcome any issues.
The GnRH agonist was retained in this protocol to take advantage of the FSH/LH “flare” effect occurring in the artificial luteal phase of oral contraceptive pretreatment follicular recruitment. However, GnRH receptors have been identified in the ovary, and, due to its relatively long half-life, GnRH agonist has been reported to suppress follicular development during stimulation. However, removing pituitary suppression entirely may lead to premature luteinization from endogenous androgens, especially in patients hypersensitive to LH.
Because of its potency, rapid onset of action, and short half-life, GnRH antagonist quickly and profoundly suppresses pituitary FSH/LH secretion. Levels of LH are lower when the GnRH antagonist is started in the late luteal phase or with menses rather than on day 6, which suggests that elevated follicular phase LH levels could be responsible for the less than anticipated outcomes seen with the standard GnRH antagonist approach compared with the long agonist protocol. Finally, starting a GnRH antagonist with menses has been reported to coordinate the growth of the developing cohort, which may prevent the emergence of a single dominant follicle.
Many patients with anovulatory cycles exhibit androgen overproduction, which can negatively influence oocyte development even during ART treatment. Because FSH confers LH sensitivity on granulosa cells before ovulation by inducing LH-receptor formation, an elevated basal FSH level may induce premature LH-receptor formation.
Estrogen “priming” of FSH receptors has been reported to slow premature follicular development and to promote granulosa cell FSH-receptor induction. Because estrogen dominance in the maturing follicle promotes growth and androgen dominance promotes apoptosis, the hormonal environment in the ovary before ovulation is critical to the chance of a given egg completing meiosis normally.