Neoadjuvant Treatment With Müllerian-Inhibiting Substance Synchronizes Follicles and Enhances Superovulation Yield

Abstract

Müllerian-inhibiting substance (MIS), also known as anti-Müllerian hormone, is thought to be a negative regulator of primordial follicle activation. We have previously reported that treatment with exogenous MIS can induce complete ovarian suppression within 5 weeks of treatment in mice. To investigate the kinetics of the return of folliculogenesis following the reversal of suppression, we treated animals with recombinant human MIS (rhMIS) protein for 40 days in adult female Nu/Nu mice and monitored the recovery of each follicle type over time. Following cessation of MIS therapy, secondary, and antral follicles returned within 30 days, along with the normalization of reproductive hormones, including LH, FSH, MIS, and Inhibin B. Furthermore, 30 days following MIS pretreatment, the number of antral follicles were significantly higher than controls, and superovulation with timed pregnant mare serum gonadotropin and human chorionic gonadotropin stimulation at this time point resulted in an approximately threefold increased yield of eggs. Use of the combined rhMIS-gonadotropin superovulation regimen in a diminished ovarian reserve (DOR) mouse model, created by 4-vinylcyclohexene dioxide treatment, also resulted in a twofold improvement in the yield of eggs. In conclusion, treatment with rhMIS can induce a reversible ovarian suppression, following which a rapid and synchronized large initial wave of growing follicles can be harnessed to enhance the response to superovulation. Therapies modulating MIS signaling may therefore augment the response to current ovarian stimulation protocols and could be particularly useful to women with DOR or poor responders to controlled ovarian hyperstimulation during in vitro fertilization.

Structure of AMH bound to AMHR2 provides insight into a unique signaling pair in the TGF-β family

“…AMH plays an important role in several reproductive functions, including Müllerian duct regression and regulation of folliculogenesis. As a result, AMH has been implicated in several reproductive disorders and cancers and is thus a target of interest in therapeutic intervention of these diseases and as a contraceptive agent also capable of protecting ovarian reserve during chemotherapy and enhancing yield during in vitro fertilization (4,6). Furthermore, because AMH is the only ligand which binds AMHR2, this makes AMH and AMHR2 ideal for therapeutic targeting, while limiting potential off target effects.…”

“…As a result, males are born with normal male reproductive organs but additionally develop a uterus and Fallopian tubes from the remaining portions of the Müllerian duct. More recently, it has been shown that AMH plays a fundamental role in the regulation and progression of follicles within the female ovary (4). Specifically, overexpression of AMH in the ovary can suppress early folliculogenesis (5).…”

“…Specifically, overexpression of AMH in the ovary can suppress early folliculogenesis (5). As such, AMH is being considered as a possible contraceptive and as a biotherapeutic to halt folliculogenesis during chemotherapy, in order to preserve follicles for subsequent cycles (4)(5)(6).…”

Single-cell sequencing reveals suppressive transcriptional programs regulated by MIS/AMH in neonatal ovaries

“…Postnatally, in females, MIS is mainly produced by granulosa cells of secondary and early antral follicles and acts through its specific receptor, MISR2 (AMHR2), which is expressed in granulosa cells of all types and in ovarian surface epithelium (OSE) (14). MIS produced by growing follicles is thought to provide a negative feedback to prevent primordial follicle activation, a function that has been supported by in vitro and in vivo studies in rodents and humans (15)(16)(17)(18).…”

Stage-dependent actions of antimüllerian hormone in regulating granulosa cell proliferation and follicular function in the primate ovary

“…Although AMH protein administration was performed in mice, prolonged systemic treatment (subcutaneous injections every 12 hours for 40 days) resulted in supraphysiologic serum levels of AMH, i.e., $1,000 ng/mL based on pharmacokinetic data for subcutaneous AMH injection in mice, relative to a physiologic level of <50 ng/mL (12)(13)(14)(15). Consequently, follicular development was completely suppressed from the early-growing to antral stage and the estrous cycles ceased (12). A negative correlation was observed between AMH expression, at mRNA and protein levels, in GCs and antral follicle sizes in rats (2) and sheep (16).…”