1. Müllerian inhibiting substance (MIS) was found to be a successful and safe contraceptive in female mice.
2. Female mice administered MIS during chemotherapy exhibited higher numbers of ovarian follicles.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Currently, MIS levels are clinically measured to determine the follicular reserve of the ovaries. This hormone is predicted to inhibit folliculogenesis in adults, making it a strong candidate for a targeted contraceptive agent and treatment for primary ovarian insufficiency. Instead of using estrogen and progesterone to target a more indirect pathway, MIS could be used more safely due to its effects on the follicle alone. This study examined the potential of MIS as a contraceptive and a protective agent against chemotherapy-induced primordial follicle depletion.
First, a viral gene therapy vector that contained MIS was generated and administered to mice. The treated mice showed a lack of growing follicles, demonstrating that there was an inhibition of follicular activation. After 6 weeks, the mice became infertile, either unable to produce normal-sized litters or any litters at all. In pregnant mice, MIS did not cross the placental barrier and had no effect on the litters produced. Next, the effect of this hormone on chemotherapy-induced primary ovarian insufficiency was tested. Mice treated with MIS and then various chemotherapeutics had higher ovarian reserves, as demonstrated by increased counts of primordial follicles.
MIS is a promising new therapy due to its safety and its efficacy as both a contraceptive and a protective agent during chemotherapy. Although more studies should be performed in more clinically relevant models, this hormone has great therapeutic potential.
In-Depth [animal study]: An AAV9 gene therapy vector was generated to produce MIS (AAV9-MIS) and administered to female mice. The ovaries were then obtained from these mice, sectioned, and stained in order to count the follicles. The ovaries from the AAV9-MIS-treated mice demonstrated significant reductions in primary follicle count (p<0.001) as well as an overall decrease in ovarian size.
The efficacy of this hormone as a contraceptive was then tested through AAV9-MIS administration followed by continuous mating. The mice that were administered low levels of this vector had reduced fertility demonstrated by small litter sizes, and those administered high vector levels were completely infertile after 6 weeks (p<0.0001). The pups born to the treated mothers did not demonstrate any negative developmental effects, showing that this hormone does not cross the placental barrier.
Finally, the protective role of this hormone during chemotherapy was assessed through tumor-containing mouse models treated with carboplatin or doxycycline. In each model, mice administered a single dose of AAV9-MIS had significantly higher primordial follicle counts (p<0.001). To test continuous administration of MIS, osmotic pumps were implanted into mice to deliver recombinant MIS at 0.6 µg/hr. These mice were then treated with the various chemotherapeutics and their ovaries were retrieved. Significantly increased numbers of primordial follicles were noted in the MIS-treated mice (p< 0.05).
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